The specific interaction of phosphoinositides with proteins is critical for a plethora of cellular processes, including cytoskeleton remodelling, mitogenic signalling, ion channel regulation and membrane traffic. The spatiotemporal restriction of different phosphoinositide species helps to define compartments within the cell, and this is particularly important for membrane trafficking within both the secretory and endocytic pathways. Phosphoinositide homoeostasis is tightly regulated by a large number of inositol kinases and phosphatases, which respectively phosphorylate and dephosphorylate distinct phosphoinositide species. Many of these enzymes have been implicated in regulating membrane trafficking and, accordingly, their dysregulation has been linked to a number of human diseases. In the present review, we focus on the inositol phosphatases, concentrating on their roles in membrane trafficking and the human diseases with which they have been associated.

INTRODUCTION

Phosphoinositides are a family of lipid molecules that play critical roles in the cell [1,2]. Derived from phosphorylation of phosphatidylinositol (PtdIns), phosphoinositides consist of two fatty acid chains that allow the molecule to insert into the cytosolic leaflet of cellular membranes: a glycerol moiety and an inositol headgroup. Phosphorylation of the inositol headgroup at one of three positions (D-3, D-4 or D-5) gives rise to seven different species of phosphoinositide, comprising three monophosphorylated phosphoinositides, three bisphosphorylated phosphoinositides and a single trisphosphorylated phosphoinositide (Figure 1). The various phosphoinositides are localized to distinct subcellular compartments or domains within compartments, with the specific localization of phosphoinositide molecules contributing to the identity of said compartments (Figure 2). Phosphoinositides serve as recruiting platforms for specific effector proteins, and thereby facilitate signal transduction, membrane trafficking and cell migration, among other functions [1,2]. Phosphoinositides can also directly influence the activity of effector proteins, as in the case of PtdIns(4,5)P2 variously activating or inhibiting several ion channels [3].

Phosphoinositide metabolism

Figure 1
Phosphoinositide metabolism

Flow diagram illustrating the structure of phosphatidylinositol and its seven phosphorylated derivatives, and the main pathways of phosphorylation and hydrolysis that interconvert them. Proteins indicated in navy blue denote phosphatases known to catalyse the indicated hydrolysis reaction. The colour of arrows signifies the phosphoinositide species being generated by the indicated reaction, with the phosphoinositides coloured as indicated in the key.

Figure 1
Phosphoinositide metabolism

Flow diagram illustrating the structure of phosphatidylinositol and its seven phosphorylated derivatives, and the main pathways of phosphorylation and hydrolysis that interconvert them. Proteins indicated in navy blue denote phosphatases known to catalyse the indicated hydrolysis reaction. The colour of arrows signifies the phosphoinositide species being generated by the indicated reaction, with the phosphoinositides coloured as indicated in the key.

Cellular distribution of phosphoinositide species

Figure 2
Cellular distribution of phosphoinositide species

Schematic depiction of the subcellular localization of the seven phosphoinositide species within the cell, illustrating the predominant locations of each phosphoinositide within the biosynthetic and endocytic pathways. The phosphoinositides are coloured as indicated in the inset box. Black triskelions represent clathrin coats. Note that, for clarity, compartments of the autophagy pathway are not shown, and consequently the pool of PtdIns3P generated at the ER during autophagosome biogenesis is not illustrated. It should be remembered that the abundance of the phosphoinositides is low, typically comprising less that 1% of total phospholipids, with PtdIns(4,5)P2 and PtdIns4P by far the most abundant species.

Figure 2
Cellular distribution of phosphoinositide species

Schematic depiction of the subcellular localization of the seven phosphoinositide species within the cell, illustrating the predominant locations of each phosphoinositide within the biosynthetic and endocytic pathways. The phosphoinositides are coloured as indicated in the inset box. Black triskelions represent clathrin coats. Note that, for clarity, compartments of the autophagy pathway are not shown, and consequently the pool of PtdIns3P generated at the ER during autophagosome biogenesis is not illustrated. It should be remembered that the abundance of the phosphoinositides is low, typically comprising less that 1% of total phospholipids, with PtdIns(4,5)P2 and PtdIns4P by far the most abundant species.

The spatiotemporal regulation of phosphoinositide production and turnover is critical for proper cellular function, and this carefully controlled balance of different phosphoinositide species is accomplished by phosphoinositide kinases and phosphatases with highly specific preferences for particular phosphoinositide species [1,2]. So far, 35 mammalian phosphatases have been identified [4], which can be divided into four groups according to their substrate specificity, with enzymes that remove phosphate moieties from the D-3, D-4 or D-5 positions designated 3-, 4- or 5-phosphatases respectively. The 3-phosphatases include myotubularins and PTEN (phosphatase and tensin homologue deleted on chromosome 10). There are four mammalian 4-phosphatases, which preferentially remove the 4-phosphate group from either PtdIns(3,4)P2 or PtdIns(4,5)P2. Ten 5-phosphatases are found in the mammalian genome. Finally, there is a fourth group of phosphatases, the SAC (suppressor of actin) phosphatases, which are able to hydrolyse phosphate groups at several positions.

Given the importance of the precise and distinct localization of phosphoinositides for a range of cellular functions, it is unsurprising that dysregulation of phosphoinositide metabolism may result in severely adverse effects for an organism. Accordingly, mutations in phosphoinositide phosphatases have been implicated in human diseases ranging from cancer and diabetes to neurological disorders and asthma. The importance of phosphoinositide phosphatases has also been underlined by studies in animal models. The role of phosphoinositide phosphatases in health and disease has been covered comprehensively in several reviews [47]. The focus of the present review is the role of the phosphoinositide phosphatases in membrane trafficking, and how perturbation of this process may lead to human disease (Table 1).

Table 1
Inositol phosphatases implicated in membrane trafficking

List of mammalian inositol phosphatases that have been implicated in one or more aspects of membrane trafficking, and that have also been associated with human disease.

Inositol phosphatase Trafficking steps implicated in Human disease associated with 
MTM1 Trafficking at early endosomes [19,25XLCNM [30
MTMR2 Trafficking at late endosomes [18CMT4B1 [34
MTMR3 Regulation of autophagy [184– 
MTMR4 Sorting and signalling at early endosomes [28,29– 
MTMR6 Regulation of autophagy [40– 
MTMR7 Regulation of autophagy [40Variant Creutzfeldt–Jakob disease [185
MTMR13 Binds to and stabilizes MTMR2 on endosomes. Likely function in endosome trafficking [186CMT4B2 [187
MTMR14 Control of autophagy induction [40XLCNM [39
INPP4A Endocytosis, endosomal phosphoinositide homoeostasis [50,51Down-regulated in temporal lobe epilepsy [56], asthma [58
TMEM55A, TMEM55B Trafficking at late endosomes and lysosomes [48– 
OCRL1 Endocytic trafficking [7072,85]; primary cilia trafficking [80]; phagocytosis [76,86Lowe syndrome [63]; Dent-2 disease [64
INPP5B Endosomal phosphoinositide homoeostasis [51]; phagocytosis [86,87]; Golgi–ER trafficking? [84– 
SYNJ1 Endocytosis [96,97Down's syndrome? [99]; mutated in some early-onset Parkinsonism patients [104
SYNJ2 Endocytosis [105– 
INPP5E Stabilization of primary cilia [111]; phagocytosis [113MORM syndrome [111]; Joubert syndrome [112
SHIP2 Endocytosis [123]; regulation of early endosome dynamics [128]; phagocytosis [130Increased expression in Type 2 diabetes [132
SAC1 Regulation of secretory trafficking [148,188– 
SAC3/FIG4 Regulation of endosome dynamics [154CMT4J [36,161]; ALS [163]; YVS [164
Inositol phosphatase Trafficking steps implicated in Human disease associated with 
MTM1 Trafficking at early endosomes [19,25XLCNM [30
MTMR2 Trafficking at late endosomes [18CMT4B1 [34
MTMR3 Regulation of autophagy [184– 
MTMR4 Sorting and signalling at early endosomes [28,29– 
MTMR6 Regulation of autophagy [40– 
MTMR7 Regulation of autophagy [40Variant Creutzfeldt–Jakob disease [185
MTMR13 Binds to and stabilizes MTMR2 on endosomes. Likely function in endosome trafficking [186CMT4B2 [187
MTMR14 Control of autophagy induction [40XLCNM [39
INPP4A Endocytosis, endosomal phosphoinositide homoeostasis [50,51Down-regulated in temporal lobe epilepsy [56], asthma [58
TMEM55A, TMEM55B Trafficking at late endosomes and lysosomes [48– 
OCRL1 Endocytic trafficking [7072,85]; primary cilia trafficking [80]; phagocytosis [76,86Lowe syndrome [63]; Dent-2 disease [64
INPP5B Endosomal phosphoinositide homoeostasis [51]; phagocytosis [86,87]; Golgi–ER trafficking? [84– 
SYNJ1 Endocytosis [96,97Down's syndrome? [99]; mutated in some early-onset Parkinsonism patients [104
SYNJ2 Endocytosis [105– 
INPP5E Stabilization of primary cilia [111]; phagocytosis [113MORM syndrome [111]; Joubert syndrome [112
SHIP2 Endocytosis [123]; regulation of early endosome dynamics [128]; phagocytosis [130Increased expression in Type 2 diabetes [132
SAC1 Regulation of secretory trafficking [148,188– 
SAC3/FIG4 Regulation of endosome dynamics [154CMT4J [36,161]; ALS [163]; YVS [164

PHOSPHOINOSITIDES AND MEMBRANE TRAFFIC

Most, if not all, of the phosphoinositides are involved directly in membrane trafficking (reviewed in [1,2]). They generally act by recruiting effector proteins to distinct membrane domains that promote the formation of trafficking intermediates, their movement to the next compartment in the trafficking pathway or their attachment and subsequent fusion at the downstream compartment. Different phosphoinositides are typically associated with different compartments and the trafficking steps that occur there (Figure 2). For example, PtdIns4P is enriched at the Golgi apparatus, where it regulates both intra-Golgi trafficking and the subsequent trafficking of cargo from the Golgi apparatus to the PM (plasma membrane) or the endosomal system [8]. The different trafficking steps are mediated by various effector proteins that bind specifically to PtdIns4P. Well-described examples are the GGA [Golgi-associated γ-adaptin ear homology domain Arf (ADP-ribosylation factor)-interacting protein] and AP (adaptor protein)-1 clathrin adaptors that participate in the biogenesis of TGN (trans-Golgi network)-derived clathrin-coated vesicles [8].

Within the endosomal system, the picture is more complex, with different phosphoinositide species acting at various steps within the pathway [9] (Figure 2). PtdIns(4,5)P2 is a key regulator of clathrin-coated vesicle formation at the PM [10]. Numerous clathrin accessory proteins including the AP-2 adaptor complex are recruited to CCPs (clathrin-coated pits) through direct binding to PtdIns(4,5)P2. PtdIns(4,5)P2 also contributes to clathrin-coated vesicle formation by promoting assembly of actin at sites of budding, which is required for carrier morphogenesis. Recently, PtdIns(3,4)P2 was also found in CCPs, and a role in recruiting distinct effectors including SNX9 (sorting nexin 9) uncovered [11]. Thus it appears that both PtdIns(4,5)P2 and PtdIns(3,4)P2 are required for formation of clathrin-coated vesicles at the PM. Additionally, PtdIns(4,5)P2 and PtdIns(3,4,5)P3 are important for actin remodelling in the context of non-clathrin-mediated uptake processes, most notably phagocytosis [12]. This is mediated by numerous actin regulators and actin-associated factors that are recruited and/or activated by PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Following internalization, endocytic vesicles deliver their content to the early endosome, which is a major hub for receptor sorting. Cargo can be recycled back to the PM, which may be direct or via the recycling endosomes, trafficked to the TGN, or sorted into intraluminal vesicles for subsequent delivery to and degradation within the lysosome. The early endosome is enriched in PtdIns3P, which recruits a number of effector proteins important for early endosomal identity and function [13]. Examples of PtdIns3P effectors are EEA1 (early endosome antigen 1), which participates in endosome tethering and fusion, and the sorting nexins, which are key components of the recycling machinery. PtdIns3P is converted into PtdIns(3,5)P2 as early endosomes mature to become MVBs (multivesicular bodies) and then late endosomes. PtdIns(3,5)P2 recruits distinct effectors to regulate traffic-king from endosomes to lysosomes as well as retrograde trafficking from endosomes to the Golgi [14]. PtdIns5P is the least well understood of the phosphoinositides. It is present at the PM and on endomembranes, as well as localizing to the nucleus, and functions in cytoskeleton regulation and stress signalling pathways [15]. A role for PtdIns5P in endosomal trafficking has been proposed, but, to date, there is little direct evidence, mainly owing to the dearth of known PtdIns5P effectors that could fulfil a trafficking function.

Given the many and important roles that phosphoinositides play in regulating membrane traffic, it follows that the enzymes controlling their abundance are key modulators of membrane traffic. As such, inositol phosphatases are present throughout the endomembrane system (Figure 3), and contribute to the myriad trafficking steps occurring there. The phosphatases and their roles in trafficking are described below.

Cellular distribution of inositol phosphatases

Figure 3
Cellular distribution of inositol phosphatases

Schematic depiction of the localization of the mammalian inositol phosphatases within the endomembrane system. Black triskelions represent clathrin coats.

Figure 3
Cellular distribution of inositol phosphatases

Schematic depiction of the localization of the mammalian inositol phosphatases within the endomembrane system. Black triskelions represent clathrin coats.

INOSITOL POLYPHOSPHATE 3-PHOSPHATASES

Phosphate moieties are removed from the D-3 position of phosphoinositides by inositol polyphosphate 3-phosphatases, which can be divided into two main groups: the myotubularin proteins, and PTEN and its homologues.

Myotubularins

The myotubularins are a group of proteins that consists of 14 family members in humans [16]. Eleven of the 14 myotubularins have been demonstrated to heterodimerize with other myotubularin proteins, with some of the proteins able to form more than one heterodimer. Eight of the myotubularins, i.e. MTM1 (myotubularin 1) and MTMR (myotubularin-related) proteins MTMR1–MTMR4 and MTMR6–MTMR8, are catalytically active, preferentially dephosphorylating PtdIns3P and PtdIns(3,5)P2 at the D-3 position. The six other myotubularin proteins do not possess any phosphatase activity, however, owing to the loss of key residues in the active site of their respective phosphatase domains. Despite this, it is thought that the catalytically inactive myotubularins can indirectly regulate phosphoinositide turnover, because heterodimerization with the active myotubularins may affect the latter's subcellular localization, ability to bind their phosphoinositide substrate or catalytic activity [16]. Furthermore, a recent study demonstrated that knockdown of catalytically inactive MTMR12 leads to a reduction in the protein levels of MTM1 in both mammalian cells and zebrafish, suggesting that heterodimerization with inactive myotubularins increases the biochemical stability of active myotubularins [17].

MTM1 and MTMR2 are localized to early and late endosomal compartments [1821] (Figure 3). Various studies have shown altered endosome morphology and PtdIns3P levels in cells in which MTM1 or MTMR2 are overexpressed or depleted, supporting a role in controlling endosomal PtdIns3P homoeostasis and membrane dynamics [18,2225]. Interestingly, MTM1 and MTMR2 can physically associate with the Vps34 (vacuolar protein sorting 34) kinase, which generates PtdIns3P from PtdIns, through binding to the adaptor molecule Vps15 [18,19]. The resulting complexes probably function to tightly control endosomal PtdIns3P levels. Similar to mammalian cells, depletion of the single MTM1/MTMR2 orthologue in Drosophila melanogaster (MTM) results in aberrant accumulation of PtdIns3P on early endosomes [26], indicating the conserved role of the proteins in endosomal PtdIns3P homoeostasis.

As expected from the ability of MTM1 and MTMR2 to alter endosomal PtdIns3P levels, both proteins have been shown to regulate endosomal membrane traffic. Depletion of MTM1 or MTMR2 perturbs growth factor receptor trafficking within the endocytic pathway [18]. In MTM1- or MTMR2-depleted cells, EGFR (epidermal growth factor receptor) accumulates in PtdIns3P-enriched early or late endosomes respectively, rather than being trafficked to the lysosome for degradation, supporting a role for MTM1 in receptor trafficking at early endosomes and MTMR2 in trafficking at late endosomes [18]. Depletion of MTMR2 has also been shown to perturb endosomal trafficking of the excitatory AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor) in neurons, where it accumulates in late endosomes, again consistent with a late endosomal trafficking function [20]. Loss of MTM1 in mammals and MTM in Drosophila results in reduced abundance of integrins at the cell cortex in muscle, with an accompanying accumulation in endosomes, supporting a role for these phosphatases in the endocytic recycling of integrins in muscle tissue [27]. This probably has pathological importance (see below). In addition to MTM1 and MTMR2, MTMR4, which has a PtdIns3P-binding FYVE domain, is also localized to endosomes [28] (Figure 3). MTMR4 regulates endosomal PtdIns3P and PtdIns(3,5)P2 levels, and, in addition to modulating TGFβ (transforming growth factor β) signalling at early endosomes, is important for transferrin receptor recycling from both early and recycling endosomes [28,29]. Together, these findings indicate that MTM1, MTMR2 and MTMR4 have important roles in regulating protein trafficking within the endocytic pathway. This is likely to be mediated by changes in the recruitment or activity of PtdIns3P- and PtdIns(3,5)P2-associated effector proteins that are required for endosomal membrane dynamics and receptor trafficking.

The physiological importance of the myotubularins is illustrated by the fact that mtm-null Drosophila die at the larval stage [26]. Although such a dramatic phenotype is not observed in mammals, perhaps given that there are multiple myo-tubularins in these organisms, mutations affecting individual myotubularins do, nonetheless, cause severe diseases (reviewed in [16]). Mutations in MTM1 are seen in approximately 90% of patients suffering from XLCNM (X-linked recessive form of centronuclear myopathy), also known as myotubular myopathy, a condition characterized by skeletal muscle weakness that normally causes premature death within a year of birth [30]. Analysis of skeletal muscle from XLCNM patients has revealed mislocalization of integrins and defective myofibre adhesion and organization, probably caused by defective endocytic trafficking, supporting a role for integrin trafficking in the pathogenesis of XLCNM [27]. Interestingly, an additional trafficking-independent role for MTMR1 function in skeletal muscle has also recently been proposed [31]. MTM1 was shown to bind to the BAR (BIN/amphiphysin/Rvs) domain protein amphiphysin 2/BIN1, which is a critical protein for T-tubule (transverse tubule) formation, and positively regulate its ability to tubulate membranes [31]. This ability is dependent on MTM1 phosphatase activity, and, following MTM1 depletion, BIN1-mediated formation of T-tubules in muscle cells is perturbed [31]. A possible mechanism is that the regulation of phosphoinositide levels by MTM1 is important for BIN1 function and thus, in the absence of functional MTM1, the reduction in BIN1-induced membrane tubulation may lead to the observed muscle weakness of XLCNM sufferers [31]. Further studies are required to determine the extent to which trafficking-dependent and -independent functions contribute to the development of XLCNM.

MTMR2 has been implicated directly in regulating myelination, a process that is highly dependent on the efficient sorting and trafficking of lipids and proteins to form the myelin membrane [32], with nerve myelination severely impaired in Mtmr2-null mice [33]. Consistent with MTMR2 being functionally important in the nervous system, mutations in MTMR2 and its binding partner MTMR13 are the causative genes of the neuropathies CMT (Charcot–Marie–Tooth) disease type 4B1 and 4B2 respectively [34,35]. CMT4 diseases are neuropathies in which myelination is dysregulated, and are characterized by severe muscular atrophy, but the precise molecular mechanisms remain to be determined [16]. However, given that mutations in one of the SAC phosphatases (see below), SAC3/FIG4, cause another subtype of CMT4 [36], it is likely that an imbalance in phosphoinositide metabolism and subsequent disruption of trafficking will be a common cause of these diseases.

Recent work has implicated the myotubularins in regulation of autophagy, a specialized pathway through which the degradation of cellular material occurs [37]. Autophagy comprises a series of membrane remodelling and trafficking steps that result in the inclusion of cellular contents within a membrane-enclosed autophagosome that subsequently fuses with lysosomes to generate autophagolysosomes, resulting in digestion of the enclosed contents. PtdIns3P plays a key role in autophagosome biogenesis, with numerous PtdIns3P effector proteins contributing to the process [37]. It is therefore not surprising that myotubularins can regulate auto-phagy. Specifically, MTMR3 and MTMR14 can suppress autophagy initiation by hydrolysing PtdIns3P [38]. Moreover, the accumulation of autophagosome-like structures in Drosophila cells depleted of MTM implies that MTM may also be involved in autophagy [26]. Interestingly, mutations in MTMR14 have been detected in XLCNM patients lacking MTM1 mutations [39]. One of these mutations renders MTMR14 catalytically inactive, and the fact that the mutant protein is unable to suppress autophagy induction suggests that dysregulation of autophagy may explain some of the defects seen in these XLCNM patients [40]. Although the myotubularins generally seem to be inhibitors of auto-phagy, the fact that the single yeast MTMR Ymr1 removes PtdIns3P to promote autophagosome completion suggests that the regulation of PtdIns3P levels by the myotubularins can regulate both early and later stages of the autophagic process [41].

Although the roles of MTM1, MTMR2 and, to a lesser extent, MTMR4 in endocytic trafficking have been fairly well studied, the majority of the myotubularins remain poorly characterized. Members of the family have been localized to a number of non-endocytic compartments within the cell, including the Golgi apparatus and the PM, suggestive of possible roles outside the endocytic pathway, but this has yet to be explored in any detail [16].

PTEN

PTEN exhibits catalytic activity towards the phosphoinositide species PtdIns3P and PtdIns(3,4)P2, in addition to activity towards serine-, threonine- and tyrosine-phosphorylated residues on proteins, but the preferred substrate of PTEN is PtdIns(3,4,5)P3, which is hydrolysed to PtdIns(4,5)P2 (reviewed in [42]). PTEN was first discovered when it was found to be mutated in multiple tumour types, and subsequent work has demonstrated that it is a potent tumour-suppressor gene. Accordingly, PTEN is one of the most frequently mutated genes in human cancer, and PTEN deletions/mutations are common in hereditary cancers such as Cowden's disease.

PTEN is predominantly localized to the cytosol, but it also dynamically associates with the PM where it hydrolyses PtdIns(3,4,5)P3 to inhibit or restrict signalling through the PI3K (phosphoinositide 3-kinase) pathway [42]. In its role as a negative regulator of the PI3K signalling pathway, PTEN controls a number of cellular processes, ranging from cell survival and proliferation to metabolism [42]. PTEN is also important for several processes that are dependent on membrane traffic, including the establishment of cell polarity [43], phagocytosis [44] and autophagy [45]. However, PTEN's involvement in these processes does not appear to be via modulation of trafficking. Instead, the effects are probably attributable to direct removal of PM PtdIns(3,4,5)P3, either to determine cell polarity or to counteract relevant PI3K-dependent signalling reactions [42].

INOSITOL POLYPHOSPHATE 4-PHOSPHATASES

The inositol polyphosphate 4-phosphatases, which hydrolyse phosphoinositides at the D-4 position of the inositol ring, are subdivided into two classes. Two enzymes, INPP4A and INPP4B (inositol polyphosphate 4-phosphatase type I and type II respectively), preferentially use PtdIns(3,4)P2 as their substrate [46,47], whereas both TMEM55A and TMEM55B (transmembrane protein 55A and 55B respectively) remove the D-4 phosphate moiety from PtdIns(4,5)P2 [48]. In addition, a class of enzymes termed the P-Rex proteins are homologous with the PtdIns(3,4)P2 phosphatases, but contain catalytically inactive phosphatase domains [49].

INPP4A

INPP4A is found on early and recycling endosomes (Figure 3), and has been implicated in the regulation of endocytic trafficking as well as regulating signalling through the PI3K pathway [50,51]. The protein is a critical component of an enzymatic cascade, centred on Rab5 and its effectors, that controls phosphoinositide homoeostasis during endocytosis. Together with the phosphoinositide 5-phosphatase INPP5B (inositol polyphosphate 5-phosphatase B), INPP4A helps to generate endosomal PtdIns3P through sequential hydrolysis of PtdIns(3,4,5)P3. INPP5B first hydrolyses PtdIns(3,4,5)P3 to PtdIns(3,4)P2, which is then hydrolysed to PtdIns3P by INPP4A [51]. The importance of INPP4A for regulation of endosomal dynamics is emphasized by the enlargement of early endosomes in cells in which INPP4A has been knocked out [50]. Furthermore, the reduced internalization of both the transferrin receptor and the glutamate NMDAR (N-methyl-D-aspartate receptor) following INPP4A depletion implies that INPP4A is a positive regulator of endocytosis [51,52]. Interestingly, PtdIns(3,4)P2 has recently been shown to play an important role in CCPs during endocytosis, mediating recruitment of clathrin accessory proteins such as SNX9 [11]. INPP4A could therefore influence clathrin-mediated endocytosis through turnover of PtdIns(3,4)P2.

Significant insight into the physiological importance of INPP4A has been gained through the study of two mouse models. The first of these, in which INPP4A was knocked out using gene targeting, die within a month of birth, exhibiting extensive neurodegeneration accompanied by involuntary movements [52]. The loss of INPP4A markedly sensitizes neurons to glutamate-mediated cell death, owing to an increase in the levels of NMDARs at the synaptic surface [52]. In a second mouse model, ‘Weeble’, which has a spontaneous mutation within the INPP4A-coding region that precludes expression of the protein, death occurs within four weeks, and mice display severe neurodegeneration that is consistent with glutamate-mediated cell death [53,54]. The experiments in mice support a critical role for INPP4A in neurons. The dramatic increase in PtdIns(3,4)P2 levels detected in cells derived from Weeble mice are consistent with a model whereby, in the absence of INPP4A, the increase in PtdIns(3,4)P2 and/or reduction in PtdIns3P levels disrupts endocytic trafficking of the NMDAR, leading to the observed neurodegenerative effects [51]. However, it cannot be ruled out that neurodegeneration in mice lacking INPP4A is caused by abnormal phosphoinositide signalling, given that the aberrant accumulation of PtdIns(3,4)P2 on endosomes may potentially cause an increase in Akt signalling there [50].

The INPP4A chromosomal region is often deleted in neurological disorders such as schizophrenia [55], and decreased INPP4A expression has been associated with temporal lobe epilepsy [56], suggesting possible involvement in the development of such disorders. In addition, INPP4A-knockout fibroblasts form tumours when transformed into mice [57], and the protein is down-regulated in asthma [58], although in these cases the phenotype is likely to be due to dysregulation of PI3K signalling via PtdIns(3,4)P2, rather than effects on membrane trafficking.

INPP4B

Two isoforms of INPP4B are produced by alternative splicing that display distinct tissue distribution and subcellular localization: the α isoform, which is predominantly cytosolic, is widely expressed, whereas the β isoform, which is localized to the Golgi apparatus, is restricted to certain tissues including the brain [59]. The functional significance of splicing and Golgi apparatus localization of INPP4Bβ has yet to be elucidated. INPP4B has not been implicated in trafficking, but, like INPP4A, it is a negative regulator of the PI3K/Akt signalling pathway [49]. Accordingly, recent work has led to the theory that INPP4B is a tumour suppressor, with INPP4B expression lost in many breast and prostate cancers, among others (reviewed in [49,60]). Moreover, the concomitant loss of both INPP4B and PTEN observed in breast cancer samples may promote further tumour progression [60]. In addition to a purported role in tumour suppression, modulation of signalling by INPP4B is also important for regulation of bone mass [61]. In this case, INPP4B hydrolyses soluble Ins(1,3,4)P3, thereby inhibiting Ca2+ signalling, activation of the NFATc1 (nuclear factor of activated T-cells, cytoplasmic 1) transcription factor and osteoclast differentiation [61]. INPP4B-knockout mice experience an increased incidence of osteoporosis, probably due to increased numbers of osteoclasts, and SNPs (single nucleotide polymorphisms) in INPP4B are associated with osteoporosis susceptibility in humans [61].

TMEM55A and TMEM55B

Mammalian PtdIns(4,5)P2 4-phosphatases are the most recently discovered inositol phosphatases, and were first identified in a search for homologues of bacterial PtdIns(4,5)P2 4-phosphatases [48]. TMEM55A and TMEM55B are ubiquitously expressed and localize to late endosomes and lysosomes within the endocytic pathway [48] (Figure 3). Consistent with a role in regulation of late endosome/lysosome function, overexpression of either protein accelerates EGFR degradation [48]. This effect appears to be mediated through increased production of PtdIns5P, supporting a role for this phosphoinositide on late endosomes or lysosomes. This possibility has, however, yet to be rigorously tested, and currently little else is known about how TMEM55A and TMEM55B may influence trafficking or other cellular processes.

INOSITOL POLYPHOSPHATE 5-PHOSPHATASES

To date, ten human phosphatidylinositol 5-phosphatases have been identified, each containing an inositol 5-phosphatase domain that confers various levels of hydrolytic activity towards PtdIns(3,5)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 [6]. In contrast with the other 5-phosphatases, the synaptojanin proteins contain an additional catalytic domain, the SAC domain, which enables them to hydrolyse the phosphoinositide species PtdIns3P, PtdIns4P and PtdIns(3,5)P2 directly to PtdIns [62] (the SAC phosphatases are considered in the next section). The 5-phosphatases are distinguished further from one another through the presence or absence of a variety of domains that mediate interaction with particular proteins, which in turn bestow specific and distinct subcellular localizations on each enzyme [6].

OCRL1

OCRL1 was first identified when mutations in the OCRL1 gene were found to be the cause of the disease oculocerebrorenal syndrome of Lowe (OCRL) [63], an X-linked disorder that predominantly affects the eyes, brain and kidneys. OCRL1 mutations also cause Dent-2 disease, a disorder with milder ocular and neurological symptoms than Lowe syndrome [64]. Ocrl1-knockout mice do not display any symptoms of Lowe syndrome, which is explained by redundancy between OCRL1 and the homologous 5-phosphatase INPP5B; the simultaneous knockout of the Ocrl1 and Inpp5b genes is embryonically lethal in mice [65]. Partial redundancy with INPP5B also probably explains why loss of OCRL1, which is widely expressed in the body, affects only certain tissues in humans. Interestingly, duplication of the OCRL1 gene was recently identified in a patient with autism, suggesting that too much OCRL1 activity is also deleterious in humans [66].

The discovery that OCRL1 is the causative gene of Lowe syndrome inspired a concerted effort to establish the protein's biological function (reviewed in [67,68]). OCRL1 hydrolyses PtdIns(4,5)P2 and PtdIns(3,4,5)P3, with the greatest catalytic activity towards PtdIns(4,5)P2 [69]. OCRL1 resides on late-stage CCPs, early and recycling endosomes, and the TGN (Figure 3), and interacts with a host of endocytic trafficking machinery, including clathrin heavy chain, α-adaptin, several Rab GTPases, and the endocytic adaptor proteins APPL1 [adaptor protein containing PH (pleckstrin homology) domain, PTB (phosphotyrosine-binding) domain and leucine zipper motif 1] and IPIP27A/B (inositol polyphosphate phosphatase-interacting protein of 27 kDa A and B; Ses1/2) [67,68]. In accordance with its subcellular localization and interaction with various trafficking machinery, roles for OCRL1 in membrane trafficking have been uncovered. In particular, OCRL1 regulates retrograde endocytic trafficking, with both knockdown of OCRL1 or ectopic expression of mutant OCRL1 lacking the 5-phosphatase domain impairing endocytic recycling of receptors to the PM and/or TGN [7072]. A role for OCRL1 in anterograde Golgi to endosome trafficking has also been suggested through its association with Rab31 [73].

PtdIns(4,5)P2 levels are elevated in cells derived from Lowe syndrome patients and in OCRL1-deficient zebrafish [74,75], and PtdIns(4,5)P2 is ectopically accumulated on endosomes in cells depleted of OCRL1 [71]. The elevation in endosomal PtdIns(4,5)P2 levels is responsible for aberrant accumulation of F-actin (filamentous actin) on endosomes, which may account for the impaired trafficking out of this compartment [71]. These findings suggest that one function of OCRL1 is to restrict PtdIns(4,5)P2 and actin abundance on endosomes. The hydrolysis of PtdIns(4,5)P2 by OCRL1 also appears to regulate actin dynamics more generally, which is important for a number of other cellular processes. For example, OCRL1 is a regulator of phagocytosis (Figure 3), hydrolysing PtdIns(4,5)P2 to promote phagosome closure through localized remodelling of actin, and attenuate PI3K signalling through removal of PtdIns(3,4,5)P3 [76,86]. OCRL1 also plays an important role in cytokinesis, hydrolysing PtdIns(4,5)P2 to remove actin from the cytokinetic bridge during abscission [77,78]. In addition, OCRL1 can regulate cell polarity [79], adhesion and migration [80], and it is conceivable that these functions of OCRL1 are also actin-dependent. Finally, OCRL1 has also recently been implicated in regulating ciliogenesis, although whether this is via regulation of actin at the cilium itself or due to defective membrane trafficking to the cilium remains to be determined [80,81].

Despite the extensive research that has been carried out to decipher the cellular role(s) of OCRL1, it is still poorly understood precisely how mutations in OCRL1 lead to the symptoms observed in Lowe syndrome and Dent-2 disease. It is likely that the manifestations of these disorders arise through a combination of the cellular defects described above, which may affect different cell types and tissues to various degrees.

INPP5B

INPP5B is widely expressed in humans and hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3 [82,83]. INPP5B has a highly similar domain organization to that of OCRL1 {indeed, they are the only two human inositol phosphatases that contain a RhoGAP (Rho GTPase-activating protein)-like domain [67]}. However, INPP5B does not interact with clathrin or α-adaptin, and is absent from CCPs [84,85]. It is, however, present in membrane ruffles and early endosomes, consistent with a function in endocytic trafficking and/or signalling (Figure 3). Together with INPP4A, INPP5B helps to generate endocytic pools of PtdIns3P through hydrolysis of PtdIns(3,4,5)P3 that is likely to be important for endosomal homoeostasis [51]. INPP5B has also been localized to phagosomes (Figure 3), where, in concert with OCRL1, it may regulate signalling and actin dynamics [86,87]. INPP5B may also play a role within the secretory pathway. It is localized to the ERGIC (endoplasmic reticulum–Golgi intermediate compartment) and Golgi apparatus (Figure 3), and overexpression of INPP5B impairs retrograde ERGIC-to-ER (endoplasmic reticulum) trafficking [84]. More recently, INPP5B has been localized to primary cilia, and depletion of INPP5B reduces cilium length and disrupts development of ciliated structures in zebrafish embryos [88]. Together, these findings suggest that INPP5B participates in a number of membrane trafficking processes.

INPP5B has not been associated with any human disease. However, male Inpp5b-knockout mice are infertile, producing deformed sperm and testes nurse Sertoli cells replete with enlarged endosome-like structures, consistent with a role in endosomal trafficking or homoeostasis [89]. Moreover, and as alluded to above, INPP5B is able to functionally compensate for loss of OCRL1 in mice [65], and probably also to some degree in humans.

SYNJ1

There are two synaptojanins in mammals, SYNJ1 and SYNJ2, which both contain an N-terminal SAC domain and a more central 5-phosphatase domain. The 5-phosphatase domains of both enzymes show greatest hydrolytic activity towards PtdIns(4,5)P2 and PtdIns(3,4,5)P3 [69]. In addition, their respective SAC domains also dephosphorylate PtdIns3P, PtdIns4P and PtdIns(3,5)P2 to PtdIns [62]. The two synaptojanins share ~55% sequence identity in their phosphatase domains, but are highly divergent in their C-terminal regions [90]. In addition, both synaptojanins are alternatively spliced. Whereas the 170 kDa splice variant of SYNJ1 is ubiquitously expressed, expression of the 145 kDa variant is more restricted, with especially high levels in the brain [90,91]. There are six SYNJ2 splice variants, with variant 2A being ubiquitously expressed, whereas splice variants 2B1 and 2B2 are expressed only in the brain and testis [90,92,93].

SYNJ1 was initially shown to interact with, and co-localize to nerve terminals with, proteins involved in synaptic vesicle endocytosis such as dynamin and amphiphysin [94]. Subsequent work demonstrated that SYNJ1 is recruited to CCPs (Figure 3), with the 170 kDa isoform present throughout CCP formation, whereas the 145 kDa isoform is recruited only during the latter stages [95]. A specific role for SYNJ1 in vesicle endocytosis was confirmed by the accumulation of clathrin-coated vesicles in mice and Caenorhabditis elegans lacking functional SYNJ1 [96,97]. SYNJ1 degrades PtdIns(4,5)P2 to facilitate clathrin uncoating, and, consequently, clathrin-mediated endocytosis is impaired in the absence of SYNJ1, with both phosphatase domains required for complete hydrolysis of PtdIns(4,5)P2 to PtdIns to enable normal vesicle internalization [98].

The functional importance of SYNJ1 is illustrated by the fact that 85% of SYNJ1-null mice die within 24 h of birth, whereas the few surviving mice suffer from neurological defects, including convulsions [96]. Accordingly, SYNJ1 has been associated with several human neurological disorders. Trisomy of chromosome 21, where SYNJ1 maps to, causes Down's syndrome, and SYNJ1 is overexpressed in both Down's syndrome patients and a mouse model of the disease [99,100]. A causative link between SYNJ1 overexpression and Down's syndrome is suggested further by the finding that the enlargement of early endosomes, a characteristic of Down's syndrome cells, can be induced by overexpression of SYNJ1 alone [100]. These studies together indicate that SYNJ1 may represent a suitable target for treatment of Down's syndrome.

SYNJ1 has also been associated with neurodegenerative disorders, in particular with AD (Alzheimer's disease). Aβ (amyloid β-peptide)-mediated toxicity contributes to AD, and work in a mouse model of AD illustrated that mice haploinsufficient for SYNJ1 were resistant to both the synaptic dysfunction and the reduction in PtdIns(4,5)P2 levels caused by Aβ [101,102]. The normalization of PtdIns(4,5)P2 levels brought about by a reduction in SYNJ1 expression may reduce Aβ toxicity by restoring neurotransmitter receptor trafficking, or through increased uptake and clearance of Aβ [102,103]. The fact that individuals with Down's syndrome, in which SYNJ1 is overexpressed, develop AD is entirely consistent with the theory that the regulation of PtdIns(4,5)P2 levels by SYNJ1 plays a role in the pathology of AD. Interestingly, mutations in SYNJ1 have also been associated with another neurological syndrome, early-onset parkinsonism [104], implying that dysregulation of SYNJ1 function, in particular with respect to neuronal endocytosis, may commonly occur in neurological disorders.

SYNJ2

In addition to the distinct tissue distribution highlighted above, SYNJ2 is structurally distinguished from SYNJ1 by the presence of unique proline-rich and C-terminal regions that facilitate interaction with distinct proteins from SYNJ1 [90]. Similarly to SYNJ1, SYNJ2 plays an important role during clathrin-mediated endocytosis (Figure 3), with depletion of SYNJ2 impairing receptor internalization and reducing the number of CCPs and vesicles [105]. These defects could not be rescued by expression of SYNJ1, suggesting that SYNJ2 acts distinctly from SYNJ1 during clathrin-mediated endocytosis, possibly at an earlier stage. SYNJ2 is distinguished further from SYNJ1 by its interaction with the small GTPase Rac1 [92,106]. Indeed, whereas expression of constitutively active Rac1 causes SYNJ2 to translocate to the PM, resulting in inhibition of clathrin-mediated endocytosis, the subcellular distribution of SYNJ1 is unaffected by expression of Rac1 [92,106].

Although a Synj2-knockout mouse has yet to be generated, a mouse strain expressing a mutated form of SYNJ2 has been reported [107]. The strain, designated Mozart, carries a mutation in the inositol 5-phosphatase domain that dramatically reduces the catalytic activity of that domain. Interestingly, Mozart mice display severe hearing loss by 12 weeks of age, concomitant with gradual loss of hair cells [107]. The absence of any other detectable phenotypic defects in these mice would suggest that, in most cells, SYNJ2 is functionally redundant with SYNJ1 and/or other inositol 5-phosphatases. It is as yet unclear precisely what role SYNJ2 plays in hair cells, and whether or not regulation of membrane trafficking is important for this function. Moreover, it remains to be seen whether the evident importance of SYNJ2 for mouse hearing also applies in humans.

INPP5E

INPP5E dephosphorylates both PtdIns(3,5)P2 and PtdIns(4,5)P2, and, additionally, is the most catalytically active of all the 5-phosphatases towards PtdIns(3,4,5)P3 [108,109]. INPP5E is ubiquitously expressed, with particularly high expression in the heart, brain and testis [108,109]. Immunofluorescence experiments demonstrate that the protein is predominantly localized to the Golgi apparatus in proliferating cells [108,110] (Figure 3), but localizes to the primary cilium in quiescent cells [111,112]. It is also found on phagocytic cups in macrophages [113] (Figure 3).

INPP5E has been implicated in membrane trafficking. Similarly to another inositol 5-phosphatase, SHIP1 [SH2 (Src homology) domain-containing inositol 5-phosphatase 1] (see below), INPP5E regulates phagocytosis by reducing the concentration of PtdIns(3,4,5)P3 on the phagocytic membrane, focally degrading this phosphoinositide to control phagosome closure [113]. Experimental overexpression of INPP5E can generate PtdIns3P at the PM, which induces insulin-independent translocation of GLUT4 (glucose transporter type 4) to the cell surface [110]. However, the mechanism by which PtdIns3P causes GLUT4 translocation, and the extent to which INPP5E contributes to the physiologically relevant GLUT4 translocation that occurs in response to insulin stimulation, remains to be determined. The presence of INPP5E at the Golgi apparatus led initially to the suggestion that it might mediate trafficking to and/or from the Golgi [108], but, to date, there is no direct evidence to support this theory.

Consistent with its localization to the primary cilium, studies using model organisms indicate that INPP5E plays a key role in regulating primary cilia homoeostasis. Inpp5e-knockout mice display defects in multiple organs, including the eyes and kidneys, that are associated with cilia defects, and the mice die soon after birth [111]. Although loss of INPP5E does not block ciliogenesis, the stability of cilia is reduced, with additional experiments suggesting that INPP5E prevents the premature disassembly of the cilium via the PI3K pathway [111,112]. The function of INPP5E in stabilizing the primary cilium is highly conserved, with mutations in INPP5E linked to a number of human ciliopathies, disorders caused by defects in primary cilia. INPP5E mutations have been detected in patients with MORM (mental retardation, truncal obesity, retinal dystrophy and micropenis) syndrome, where truncated INPP5E fails to distribute properly along the length of the cilium, instead being limited to one end [111], and Joubert syndrome, with cases of the latter disorder caused by mutations in the 5-phosphatase domain of INPP5E [112]. Furthermore, the knockdown of inpp5e in zebrafish results in widespread developmental defects, including those that affect the brain and kidneys, and both the length and number of primary cilia are decreased [114]. Taken together, data from studies in model organisms and human ciliopathies strongly support the supposition that INPP5E plays an important role in the primary cilium. The fact that mutations within the 5-phosphatase domain cause Joubert syndrome suggests that regulation of phosphoinositide metabolism by INPP5E is important in the cilium [112]. Blocking PI3K signalling restores cilium stability in cells in which INPP5E is inactivated, suggesting that INPP5E probably maintains primary cilium stability through modulation of signalling rather than regulation of membrane trafficking to/from the cilium [111].

In addition to being linked to the aforementioned ciliopathies, several studies have associated INPP5E with cancer. These studies have variously found INPP5E to be up- or down-regulated in a variety of cancers [4]. The contrasting expression profiles of INPP5E in different cancers imply that specific cancers may differentially usurp INPP5E-regulated pathways, although it remains to be seen what role, if any, INPP5E plays in cancer progression.

SHIP1

SHIP1 and SHIP2 are closely related proteins, containing similar SH2 and inositol 5-phosphatase domains but highly divergent C-terminal proline-rich regions [115]. SHIP1, which is alternatively spliced, has a restricted tissue distribution. Two splice variants, SHIP1α and SHIP1δ, are restricted to haemopoietic and spermatogenic cells, whereas the third variant, s-SHIP1, which lacks the SH2 domain, is expressed only in stem cells [116,117]. SHIP1 hydrolyses PtdIns(3,4,5)P3 and thus, similarly to PTEN, plays an important role in terminating PtdIns(3,4,5)P3-dependent signalling. In particular, SHIP1 is a critical negative regulator of the PI3K/Akt pathway and has, accordingly, been shown to inhibit the proliferation, differentiation and/or survival of a multitude of haemopoietic cells, including B- and T-cells, osteoclasts and platelets (reviewed in [118]). Some studies have implicated SHIP1 in regulation of phagocytosis, with the protein degrading PtdIns(3,4,5)P3 on the phagocytic membrane to promote phagosome closure in a manner analogous to INPP5E [113,119] (Figure 3). SHIP1 mutations and/or inactivation have been identified in several human myelomas [118], although this is probably explained by the protein's role as an inhibitor of the PI3K/Akt pathway.

SHIP2

SHIP2 is more widely expressed than the SHIP1 isoforms, with particularly high levels observed in heart, muscle and placental tissue [115,120]. In addition to hydrolysing PtdIns(3,4,5)P3, SHIP2 also displays 5-phosphatase activity towards PtdIns(4,5)P2 and PtdIns(3,5)P2 [121123]. SHIP2 is found in the cytosol and in focal adhesions, and growth factor stimulation induces its redistribution to membrane ruffles [124,125]. SHIP2 has been shown to interact with a number of proteins, and these interactions govern SHIP2 regulation of a variety of cellular functions (reviewed in [4]). These include regulation of growth factor signalling through Akt, most notably downstream of insulin, as well modulation of cell adhesion and migration. For the latter, SHIP2 can bind to various actin-associated proteins including RhoA and filamins A and B to locally regulate PtdIns(3,4,5)P3 levels and actin dynamics required for directed cell migration [124126].

In contrast with SHIP1, direct roles have been ascribed for SHIP2 in membrane trafficking. SHIP2 associates with CCPs in the early stages of their genesis (Figure 3), acting to ensure proper maturation of these structures by locally hydrolysing both PtdIns(3,4,5)P3 and PtdIns(4,5)P2, with depletion of SHIP2 accelerating CCP turnover through an increase in the concentration of these phosphoinositide species [123]. Consistent with dysregulation of membrane trafficking, SHIP2 depletion enhances the rates of endocytosis and degradation of the EGFR, ephrin receptor and CXCR4 (CXC chemokine receptor 4) [127129]. In addition to its function in clathrin-mediated endocytosis, SHIP2 also plays a role in phagocytosis, translocating to phagosomes to regulate Rac signalling and actin polymerization in a manner that is independent of SHIP1 [130] (Figure 3).

A Ship2-knockout mouse has been described, and, although it is viable, it is more insulin-sensitive than control littermates when maintained on a high-fat diet [131]. Consistent with the theory that SHIP2 negatively regulates insulin signalling, SHIP2 SNPs that increase protein expression and catalytic activity have been detected in several diabetes cohorts [132]. Therefore SHIP2 may contribute to development of Type 2 diabetes, probably through its effects on Akt signalling, and thus may represent an appropriate target for treatment of the disease. Besides having a purported role in diabetes, SHIP2 has also been implicated in cancer, where its inhibition of Akt signalling would be predicted to impair cell proliferation. However, SHIP2 expression can be elevated or reduced in different cancers, suggesting that the effects of SHIP2 on tumorigenesis varies between different types of tumour [132].

INPP5K/SKIP

SKIP (skeletal muscle and kidney inositol phosphatase) (also known as INPP5K) hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, exhibiting greatest activity towards PtdIns(4,5)P2 [69,133,134]. Although SKIP is ubiquitously expressed, especially high levels of the protein are observed in skeletal muscle and kidney [133]. SKIP is predominantly found in the ER (Figure 3), although it translocates to PM ruffles in response to epidermal growth factor stimulation [134]. Insulin treatment similarly causes SKIP to translocate to the PM [135]. Ectopic SKIP expression impairs insulin-induced GLUT4 translocation to the PM, but this inhibitory activity is brought about through inhibition of Akt signalling rather than a direct role in GLUT4 trafficking itself [135]. Moreover, despite residing in the ER, there is as yet no evidence to suggest that SKIP plays a role in trafficking from and/or to the ER. Furthermore, although dysregulation of SKIP expression has been detected in some cancers [4], there is no evidence yet to suggest that this is related to regulation of trafficking by SKIP.

INPP5J/PIPP

PIPP (proline-rich inositol polyphosphate 5-phosphatase) hydrolyses PtdIns(4,5)P2 and PtdIns(3,4,5)P3 [136,137]. PIPP localizes to PM ruffles and to neurite growth cones [136,137]. Only a few studies have examined the in vivo function of PIPP, and none of these have suggested that the phosphatase is a regulator of membrane trafficking. It has, however, been implicated in regulating Akt signalling, which is likely to be relevant during tumorigenesis [138], as well as neurite growth [137].

INPP5A

Unlike the other inositol 5-phosphatases, INPP5A hydrolyses only soluble inositol phosphate species [139]. INPP5A has not to date been implicated in membrane trafficking. Rather, it appears to regulate intracellular Ca2+ through modulation of Ins(1,4,5)P3 levels, which is important for dendritic spine morphogenesis in neurons and tumorigenesis more generally [140,141]. Interestingly, overexpression of INPP5A, and the concomitant reduction in Ca2+ signalling this produces, has been shown to alleviate symptoms of the neurodegenerative disorder spinocerebellar ataxia 2 in a mouse model of the disease [142].

SAC PHOSPHATASES

There are three mammalian SAC phosphatases, SAC1, SAC2/INPP5F and SAC3/FIG4, and each of them contains a SAC domain that confers hydrolytic activity towards distinct phosphoinositide species. Apart from the SAC domain, the SAC phosphatases display little homology with one another, differing significantly in length, and with SAC1 containing a transmembrane domain that is absent from the other two SAC phosphatases [143].

SAC1

SAC1 dephosphorylates PtdIns3P, PtdIns4P and PtdIns(3,5)P2 to PtdIns, exhibiting greatest activity towards PtdIns3P and PtdIns4P [144]. The protein is localized to the ER and the Golgi apparatus [144,145] (Figure 3), and has been heavily implicated in membrane trafficking. In quiescent cells, SAC1 is trafficked from the ER to the Golgi, where it depletes PtdIns4P to inhibit secretory trafficking [146]. In response to growth factor stimulation, SAC1 shuttles back to the ER in a COPI (coatomer protein 1)-dependent manner, leading to the accumulation of PtdIns4P within the Golgi and resumption of trafficking [146]. SAC1 control of Golgi-localized PtdIns4P is important not only for anterograde trafficking at the Golgi, but also for proper localization of Golgi enzymes and efficient cargo protein glycosyla-tion [146148].

Sac1-knockout mice exhibit pre-implantation lethality [149], and the knockdown of sac1 causes neurodegeneration in Drosophila, probably due to dysregulation of PtdIns4P [150]. Although SAC1 has not been demonstrably associated with any human disease, overexpression of the enzyme inhibits replication of the hepatitis C virus, owing to a reduction in PtdIns4P levels at the sites of viral replication [151]. Although the relevant PtdIns4P effector proteins for viral replication and their mode of action remain to be identified, the results suggest that SAC1 may be a promising target for controlling hepatitis C infection, although any modulation of SAC1 levels would have to be cell-type-specific to prevent inhibition of protein secretion throughout the body.

SAC2/INPP5F

The ubiquitously expressed SAC2 dephosphorylates PtdIns(4,5)P2 and PtdIns(3,4,5)P3 at the D-5 position [152]. SAC2 has only been characterized to a limited degree, and there is no evidence to indicate that it plays a role in membrane trafficking. Knocking out Sac2 in mice leads to stress-induced cardiac hypertrophy, but this is most likely to be due to hyperactivation of the PI3K/Akt signalling pathway [153].

SAC3/FIG4

Mammalian SAC3 (FIG4 in yeast) is broadly expressed and preferentially removes the D-5 phosphate moiety from PtdIns(3,5)P2, in addition to displaying a lower degree of catalytic activity towards PtdIns(4,5)P2 and PtdIns(3,4,5)P3 [154,155]. SAC3 is localized to various compartments within the cell, with particular enrichment on early endosomes [154,155] (Figure 3). Accordingly, the protein has been implicated in endocytic trafficking. SAC3 is an important arbiter of PtdIns(3,5)P2, forming a complex with the PtdIns3P 5-kinase PIKfyve that regulates PtdIns(3,5)P2 levels on early and late endosomes [154]. Interestingly, SAC3 activates PIKfyve kinase activity, allowing the complex to mediate rapid turnover of endosomal pools of PtdIns(3,5)P2 [156]. The SAC3/PIKfyve complex controls endosomal trafficking, most notably endosomal maturation and generation of MVBs on the degradative route of the endocytic pathway [154]. The complex, by modulating endosomal PtdIns(3,5)P2, also appears to regulate endosome to TGN trafficking, probably through effector proteins distinct from those mediating MVB formation [157]. The ancillary fact that overexpression of SAC3 promotes neurite outgrowth is consistent with SAC3 being an important regulator of endocytic trafficking, although SAC3 could also be regulating secretory trafficking in this situation [155].

‘Pale tremor’ mice, which exhibit degeneration of the central nervous system and die within six weeks of birth, result from spontaneously occurring mutations in Sac3 that abrogate its expression [36]. Neurons from these mice have decreased PtdIns(3,5)P2 levels (due to low activity of the SAC3/PIKfyve complex) and enlarged vacuoles that are positive for the lysosomal marker LAMP2 (lysosome-associated membrane protein 2) [36,158]. These data strongly suggest that, in the absence of functional SAC3, the resultant dysregulation of PtdIns(3,5)P2 leads to impaired endocytic trafficking and defective lysosomal function, ultimately leading to neuronal death [159]. Consistent with this theory, re-expression of SAC3 in neurons is sufficient to prevent spongiform degeneration in the pale tremor mouse [160]. Although autophagic markers are found in the inclusion bodies of Sac3-knockout mice, consistent with a role for the SAC3–PIKfyve complex in regulating autophagy [37], it has been proposed this effect of SAC3 deficiency is secondary to the endolysosomal trafficking defects and does not contribute significantly to the pale tremor phenotype [159]. Some pathological aspects of the pale tremor mouse are similar to those seen in patients with the neurodegenerative disorder CMT disease. Indeed, mutations in SAC3 cause CMT4J, with cells derived from CMT4J patients displaying vacuoles positive for LAMP2 [161]. One of the mutations, encoding I41T, retains catalytic activity, but is rapidly degraded [162]. Interestingly, overexpression of the I41T mutant can rescue lethality of the Sac3-knockout mouse, suggesting that it may be possible to alleviate the symptoms of CMT4J by stabilizing the mutant form of the protein [162].

In addition to causing CMT4J, SAC3 mutations have also been identified in other neurodegenerative diseases. Deleterious SAC3 mutations have been detected in ALS (amyotrophic lateral sclerosis) patients [163]. The fact that ALS patients retain one wild-type SAC3 allele, whereas CMT4J patients have two mutated alleles, where one is non-functional and the second retains reduced function, probably explains the later onset of disease in the ALS patients [163]. Consistent with this, whereas CMT4J arises in patients retaining a single, partially functional, SAC3 allele, mutations that result in complete loss of SAC3 function cause the autosomal recessive disorder YVS (Yunis–Varón syndrome) [164]. YVS is characterized by neurodegeneration, but also results in skeletal and other abnormalities. The appearance of enlarged vacuoles in YVS patient cells is reminiscent of the defects seen in the pale tremor mouse, and adds further credence to the theory that SAC3 is an important regulator of endocytic trafficking. The presence of SAC3 in inclusion bodies from a number of other neurodegenerative diseases [165], including Parkinson's and dementia, suggests that SAC3 may play a common role in the pathology of many neurodegenerative diseases.

BACTERIAL EXPLOITATION OF INOSITOL PHOSPHATASES

In addition to the human diseases that the various inositol phosphatases have been linked to, as highlighted in the preceding sections, inositol phosphatase activity is frequently exploited by intracellular pathogens during infection. This may involve either direct subversion of the host's own inositol phosphatase activity for the pathogen's benefit, or the utilization of a phosphatase encoded within the pathogen's genome. Pathogenic appropriation of host phosphoinositide metabolism has been reviewed in detail [166,167]. A few examples that relate to membrane trafficking will be considered briefly in this section.

Several host inositol phosphatases have been implicated in bacterial infection of cells. For example, enteropathogenic Escherichia coli recruits SHIP2 to the cell surface, with SHIP2 hydrolysing PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, which in turn induces formation of actin pedestals that promote bacterial growth [168]. Two other inositol 5-phosphatases, OCRL1 and INPP5B, are required for infection of host cells by Yersinia, being recruited to Yersinia-containing pre-vacuoles at the PM to hydrolyse PtdIns(4,5)P2 and promote release of mature vacuoles into the cytoplasm [169]. OCRL1 is also required for efficient infection by Chlamydia, in this case being recruited to intracellular inclusions formed by the pathogen to help to maintain a phosphoinositide composition compatible with maintenance of the inclusion [170]. OCRL1 can also be recruited to internalization sites formed by invading Listeria monocytogenes, where it probably regulates actin dynamics [171], and to intracellular pre-replicative vacuoles formed by Legionella pneumophila, where it may contribute to generation of PtdIns4P important for vacuole maintenance [172].

In addition to hijacking host-encoded inositol phosphatases, a number of bacteria utilize their own inositol phosphatases in order to promote infection, survival and/or growth in host cells. The first PtdIns(4,5)P2 4-phosphatase to be identified, the virulence factor IpgD, was discovered in the dysentery-inducing bacterium Shigella flexneri [173]. The removal of PtdIns(4,5)P2 by IpgD drastically alters the morphology of the host cell through rearrangement of the cytoskeleton, causing membrane ruffling to promote host cell entry [173]. Concomitant production of PtdIns5P by IpgD is responsible for altering endocytic trafficking of EGFR, by an unknown mechanism, resulting in sustained signalling and increased host cell survival [174]. Salmonella enterica, a major cause of food poisoning, also induces alteration of the host cell membrane, as well as modulating trafficking. The bacterially encoded SopB/SigD, which preferentially hydrolyses PtdIns(3,4)P2, PtdIns(3,5)P2 and PtdIns(3,4,5)P3 [175,176], is essential for phagosome formation during Salmonella infection [177]. Following uptake, production of PtdIns3P by SopB recruits trafficking machinery to Salmonella-containing vacuoles to modulate membrane trafficking [177]. A third example is the causative agent of tuberculosis, Mycobacterium tuberculosis, which produces the phosphoinositide phosphatase SapM, which, in contrast with Salmonella, maintains PtdIns3P-free phagosomes to prevent fusion with late endosomes [178]. These bacterial effector proteins are united by their ability to modify host membrane identity for the benefit of the pathogenic bacterium.

CONCLUDING REMARKS

The work considered in the present review underlines the importance of many of the inositol phosphatases for proper regulation of membrane trafficking, as well as illustrating the diseases that can result if phosphoinositide metabolism is dysregulated. As illustrated in Figure 3, there are numerous phosphatases associated with the various compartments of the endomembrane system, and most, if not all, compartments have several different phosphatases associated with them, many with similar or overlapping substrate preferences. This complexity probably reflects the multitude of phosphoinositide-dependent processes occurring at the various compartments, and the importance of regulating these processes with high fidelity. In some cases, different enzymes may act on common phosphoinositide pools, whereas, in many cases, it is likely that different phosphatases will be acting on discrete pools of phosphoinositides within the same compartment. This may even be the case for the same phosphoinositide species. For example, PtdIns3P regulates a number of different endosomal functions, including formation of recycling carriers and generation of intraluminal vesicles during MVB formation [9]. Different effectors mediate these distinct processes, and it is likely that they are dependent upon distinct functional pools of PtdIns3P that are differentially regulated. Untangling which inositol phosphatases regulate which phosphoinositide pools, and how they do so, is not trivial, and will rely on ever-improving techniques to localize phosphoinositides and dissect their functional roles, as well as better tools to manipulate the phosphatases themselves [179,180]. Identification of novel phosphoinositide-binding effector proteins should also prove informative.

A question that naturally arises when considering the inositol phosphatases is whether the phosphatase activity is important because of the phosphoinositide that the particular phosphatase removes, or because of the phosphoinositide it generates. The simple answer is that it varies according to the phosphatase under consideration. Whereas the removal of PtdIns(4,5)P2 by 5-phosphatases such as SYNJ1, SYNJ2 and SHIP2 is of critical importance during clathrin-mediated endocytosis [98,105,123], the dephosphorylation of PtdIns(3,5)P2 by myotubularins probably produces a significant proportion of cellular PtdIns5P [181]. Similarly, the generation of PtdIns3P on endosomes relies at least in part upon the hydrolytic activity of INPP4A and INPP5B [51]. This sequential action of INPP4A and INPP5B, converting PtdIns(3,4,5)P3 into PtdIns3P, was the first example of a cascade of inositol phosphatases functioning together to control phosphoinositide turnover and downstream cellular processes.

A frequently observed feature is the formation of protein complexes containing both inositol kinases and phosphatases, with the regulated activity of the two enzymes balancing the synthesis and hydrolysis of particular phosphoinositide species. For example, SAC3, together with the PtdIns3P 5-kinase PIKfyve and the regulatory protein ArPIKfyve, form the PAS (PIKfyve–ArPIKfyve–Sac3) complex, which governs synthesis and hydrolysis of PtdIns(3,5)P2 to tightly control homoeostasis of this phosphoinositide and endosomal progression [154]. Analogously, the myotubularins MTM1 and MTMR2 form similar tripartite complexes, in this case with the phosphoinositide 3-kinase Vps34 and its adaptor protein Vps15, to regulate PtdIns3P levels on endosomes [18,19]. Similarly, the inactive phosphatase MTMR13 forms a complex with MTM and class II PI3K to regulate endosomal PtdIns3P levels and trafficking in Drosophila [182].

When considering the plethora of mammalian inositol phosphatases, one facet that becomes immediately clear is the abundance of inositol 5-phosphatases. Although there are two types of inositol polyphosphate 3-phosphatase (acknowledging that there are eight catalytically active myotubularins) and four inositol polyphosphate 4-phosphatases, the human genome encodes ten inositol polyphosphate 5-phosphatases. Moreover, whereas the myotubularins display a broadly high degree of homology with one another, the 5-phosphatases are relatively divergent, containing a wide and unique array of domains in addition to their shared 5-phosphatase domain. The abundance of 5-phosphatases implies a requirement for exquisite regula-tion of the various 5-phosphate-containing phosphoinositides, perhaps due to the wide-ranging function of these substrates. This hypothesis is supported by the differential subcellular localization and tissue distribution of the 5-phosphatases.

Although it is clear that the enzymatic activity of the phosphoinositide phosphatases is key to their function, the addi-tional protein-interacting domains found in many of these proteins are also important. As mentioned above, such interacting domains can promote binding to a phosphoinositide kinase. However, in many cases, the interacting domains mediate binding to scaffolding proteins that help to govern the precise spatiotemporal regulation of the phosphatase. This is key in ensuring that phosphatase acts upon the correct phosphoinositide pool at the correct moment. It should also be remembered that the ability of certain phosphatases to interact with several partners, and hence act as a scaffold for these partners, could also serve an important function in its own right.

Although it is well established that phosphoinositide phosphatases function in many aspects of membrane traffic, the role of these enzymes during autophagy is currently understood only in a somewhat fragmentary respect. PtdIns3P production is essential during autophagosome generation, and a number of inositol 3-kinases have accordingly been demonstrated to play critical roles in this pathway [37]. Consistent with this, several of the myotubularins negatively regulate autophagy through hydrolysis of PtdIns3P [16]. However, it has recently emerged that, in addition to PtdIns3P, PtdIns(3,5)P2, PtdIns(3,5)P2, PtdIns4P and PtdIns(4,5)P2 may also play important roles during autophagy, particularly in the later stages of the pathway [37], although it remains to be seen whether these phosphoinositide species act in a direct or indirect manner. Accordingly, it will be interesting to find out what role (if any) the inositol 4- and/or 5-phosphatases play in the various stages of autophagy.

Another poorly understood aspect of phosphoinositide metabolism is the function of the PtdIns(4,5)P2 4-phosphatases, TMEM55A and TMEM55B. Only two papers have reported work on these two enzymes [48,183], and the role they play in health and disease largely remains mysterious. Although PtdIns5P is the least well studied of the phosphoinositides, its function is slowly becoming clearer [15], and so greater characterization of the PtdIns(4,5)P2 4-phosphatases that generate this phosphoinositide could unearth important and novel roles for these enzymes.

In the last few years, it has become clear that many of the inositol phosphatases play critical roles in the regulation of membrane trafficking. Moreover, dysregulation of these enzymes has been linked to human diseases, either directly, such as mutations in SAC3 and OCRL1 causing YVS [164] and Lowe syndrome or Dent-2 disease respectively [67,68], or indirectly, with many of the phosphatases found to be down- or up-regulated in cancer and other diseases. Although membrane trafficking defects are the likely cause of the pathology in some of these diseases, the situation is less clear for others. Thus the role of the respective phosphatase, and in particular the importance of regulation of membrane trafficking by the phosphatase, in the pathology of many diseases is unclear. It is to be hoped that work over the next few years will further our understanding of the function of these enzymes in disease progression, and that such studies will contribute to the development of therapeutics. With respect to the latter, small-molecule ‘modulators’ of inositol phosphatases have been identified [118,189], and so it will be fascinating to observe what potential drugs emerge in this exciting field over the next few years.

Abbreviations

     
  • amyloid β-peptide

  •  
  • AD

    Alzheimer’s disease

  •  
  • ALS

    amyotrophic lateral sclerosis

  •  
  • AP

    adaptor protein

  •  
  • CCP

    clathrin-coated pit

  •  
  • CMT

    Charcot–Marie–Tooth

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • ER

    endoplasmic reticulum

  •  
  • ERGIC

    endoplasmic reticulum–Golgi intermediate compartment

  •  
  • GLUT4

    glucose transporter type 4

  •  
  • INPP4

    inositol polyphosphate 4-phosphatase

  •  
  • INPP5

    inositol polyphosphate 5-phosphatase

  •  
  • LAMP2

    lysosome-associated membrane protein 2

  •  
  • MORM

    mental retardation, truncal obesity, retinal dystrophy and micropenis

  •  
  • MTM

    myotubularin

  •  
  • MTMR

    myotubularin-related

  •  
  • MVB

    multivesicular body

  •  
  • NMDAR

    N-methyl-D-aspartate receptor

  •  
  • OCRL

    oculocerebrorenal syndrome of Lowe

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PIPP

    proline-rich inositol polyphosphate 5-phosphatase

  •  
  • PM

    plasma membrane

  •  
  • PTEN

    phosphatase and tensin homologue deleted on chromosome 10

  •  
  • SAC

    suppressor of actin

  •  
  • SH2

    Src homology 2

  •  
  • SHIP

    SH2 domain-containing inositol 5-phosphatase

  •  
  • SKIP

    skeletal muscle and kidney inositol phosphatase

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • SNX9

    sorting nexin 9

  •  
  • SYNJ

    synaptojanin

  •  
  • TGN

    trans-Golgi network

  •  
  • TMEM55

    transmembrane protein 55

  •  
  • T-tubule

    transverse tubule

  •  
  • Vps

    vacuolar protein sorting

  •  
  • XLCNM

    X-linked recessive form of centronuclear myopathy

  •  
  • YVS

    Yunis–Varón syndrome

We thank Professor Viki Allan and Dr Tim Levine for a critical reading of the review. We apologize to those authors whose work we did not cite due to space constraints.

FUNDING

P.G.B. is funded by a research grant from the Medical Research Council [grant number MR/K000810/1]. Work in the Lowe laboratory is additionally supported by the Biotechnology and Biological Sciences Research Council [grant number BB/I007717/1] and Lowe Syndrome Trust [grant numbers MU/ML/1010 and ML/MU/2012].

References

References
1
Di Paolo
G.
De Camilli
P.
Phosphoinositides in cell regulation and membrane dynamics
Nature
2006
, vol. 
443
 (pg. 
651
-
657
)
[PubMed]
2
Balla
T.
Phosphoinositides: tiny lipids with giant impact on cell regulation
Physiol. Rev.
2013
, vol. 
93
 (pg. 
1019
-
1137
)
[PubMed]
3
Suh
B.-C.
Hille
B.
Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate
Curr. Opin. Neurobiol.
2005
, vol. 
15
 (pg. 
370
-
378
)
[PubMed]
4
Hakim
S.
Bertucci
M.
Conduit
S.
Vuong
D.
Mitchell
C.
Falasca
M.
Inositol polyphosphate phosphatases in human disease
Phosphoinositides and Disease
2012
Dordrecht
Springer
(pg. 
247
-
314
)
5
McCrea
H. J.
De Camilli
P.
Mutations in phosphoinositide metabolizing enzymes and human disease
Physiology
2009
, vol. 
24
 (pg. 
8
-
16
)
[PubMed]
6
Ooms
L. M.
Horan
K. A.
Rahman
P.
Seaton
G.
Gurung
R.
Kethesparan
D. S.
Mitchell
C. A.
The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease
Biochem. J.
2009
, vol. 
419
 (pg. 
29
-
49
)
[PubMed]
7
Liu
Y.
Bankaitis
V. A.
Phosphoinositide phosphatases in cell biology and disease
Prog. Lipid Res.
2010
, vol. 
49
 (pg. 
201
-
217
)
[PubMed]
8
De Matteis
M. A.
Wilson
C.
D’Angelo
G.
Phosphatidylinositol-4-phosphate: the Golgi and beyond
BioEssays
2013
, vol. 
35
 (pg. 
612
-
622
)
[PubMed]
9
Cullen
P. J.
Carlton
J. G.
Balla
T.
Wymann
M.
York
J. D.
Phosphoinositides in the mammalian endo-lysosomal network
Phosphoinositides II: the Diverse Biological Functions
2012
Dordrecht
Springer
(pg. 
65
-
110
)
10
McMahon
H. T.
Boucrot
E.
Molecular mechanism and physiological functions of clathrin-mediated endocytosis
Nat. Rev. Mol. Cell Biol.
2011
, vol. 
12
 (pg. 
517
-
533
)
[PubMed]
11
Posor
Y.
Eichhorn-Gruenig
M.
Puchkov
D.
Schöneberg
J.
Ullrich
A.
Lampe
A.
Müller
R.
Zarbakhsh
S.
Gulluni
F.
Hirsch
E.
, et al. 
Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
Nature
2013
, vol. 
499
 (pg. 
233
-
237
)
[PubMed]
12
Yeung
T.
Ozdamar
B.
Paroutis
P.
Grinstein
S.
Lipid metabolism and dynamics during phagocytosis
Curr. Opin. Cell Biol.
2006
, vol. 
18
 (pg. 
429
-
437
)
[PubMed]
13
Schink
K. O.
Raiborg
C.
Stenmark
H.
Phosphatidylinositol 3-phosphate, a lipid that regulates membrane dynamics, protein sorting and cell signalling
BioEssays
2013
, vol. 
35
 (pg. 
900
-
912
)
[PubMed]
14
Ho
C. Y.
Alghamdi
T. A.
Botelho
R. J.
Phosphatidylinositol-3,5-bisphosphate: no longer the poor PIP2
Traffic
2012
, vol. 
13
 (pg. 
1
-
8
)
[PubMed]
15
Viaud
J.
Boal
F.
Tronchère
H.
Gaits-Iacovoni
F.
Payrastre
B.
Phosphatidylinositol 5-phosphate: a nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics
BioEssays
2013
 
doi:10.1002/bies.20130132
16
Hnia
K.
Vaccari
I.
Bolino
A.
Laporte
J.
Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology
Trends Mol. Med.
2012
, vol. 
18
 (pg. 
317
-
327
)
[PubMed]
17
Gupta
V. A.
Hnia
K.
Smith
L. L.
Gundry
S. R.
McIntire
J. E.
Shimazu
J.
Bass
J. R.
Talbot
E. A.
Amoasii
L.
Goldman
N. E.
, et al. 
Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish
PLoS Genet.
2013
, vol. 
9
 pg. 
e1003583
 
[PubMed]
18
Cao
C.
Backer
J. M.
Laporte
J.
Bedrick
E. J.
Wandinger-Ness
A.
Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking
Mol. Biol. Cell
2008
, vol. 
19
 (pg. 
3334
-
3346
)
[PubMed]
19
Cao
C.
Laporte
J.
Backer
J. M.
Wandinger-Ness
A.
Stein
M.-P.
Myotubularin lipid phosphatase binds the hVPS15/hVPS34 lipid kinase complex on endosomes
Traffic
2007
, vol. 
8
 (pg. 
1052
-
1067
)
[PubMed]
20
Lee
H. W.
Kim
Y.
Han
K.
Kim
H.
Kim
E.
The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains excitatory synapses by modulating endosomal traffic
J. Neurosci.
2010
, vol. 
30
 (pg. 
5508
-
5518
)
[PubMed]
21
Franklin
N. E.
Taylor
G. S.
Vacratsis
P. O.
Endosomal targeting of the phosphoinositide 3-phosphatase MTMR2 is regulated by an N-terminal phosphorylation site
J. Biol. Chem.
2011
, vol. 
286
 (pg. 
15841
-
15853
)
[PubMed]
22
Taylor
G. S.
Maehama
T.
Dixon
J. E.
Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate
Proc. Natl. Acad. Sci. U.S.A.
2000
, vol. 
97
 (pg. 
8910
-
8915
)
[PubMed]
23
Blondeau
F.
Laporte
J.
Bodin
S.
Superti-Furga
G.
Payrastre
B.
Mandel
J. L.
Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway
Hum. Mol. Genet.
2000
, vol. 
9
 (pg. 
2223
-
2229
)
[PubMed]
24
Laporte
J.
Liaubet
L.
Blondeau
F.
Tronchère
H.
Mandel
J.-L.
Payrastre
B.
Functional redundancy in the myotubularin family
Biochem. Biophys. Res. Commun.
2002
, vol. 
291
 (pg. 
305
-
312
)
[PubMed]
25
Chaussade
C.
Pirola
L.
Bonnafous
S.
Blondeau
F.
Brenz-Verca
S.
Tronchère
H.
Portis
F.
Rusconi
S.
Payrastre
B.
Laporte
J.
Van Obberghen
E.
Expression of myotubularin by an adenoviral vector demonstrates its function as a phosphatidylinositol 3-phosphate [PtdIns(3)P] phosphatase in muscle cell lines: involvement of PtdIns(3)P in insulin-stimulated glucose transport
Mol. Endocrinol.
2003
, vol. 
17
 (pg. 
2448
-
2460
)
[PubMed]
26
Velichkova
M.
Juan
J.
Kadandale
P.
Jean
S.
Ribeiro
I.
Raman
V.
Stefan
C.
Kiger
A. A.
Drosophila Mtm and class II PI3K coregulate a PI(3)P pool with cortical and endolysosomal functions
J. Cell Biol.
2010
, vol. 
190
 (pg. 
407
-
425
)
[PubMed]
27
Ribeiro
I.
Yuan
L.
Tanentzapf
G.
Dowling
J. J.
Kiger
A.
Phosphoinositide regulation of integrin trafficking required for muscle attachment and maintenance
PLoS Genet.
2011
, vol. 
7
 pg. 
e1001295
 
[PubMed]
28
Naughtin
M. J.
Sheffield
D. A.
Rahman
P.
Hughes
W. E.
Gurung
R.
Stow
J. L.
Nandurkar
H. H.
Dyson
J. M.
Mitchell
C. A.
The myotubularin phosphatase MTMR4 regulates sorting from early endosomes
J. Cell Sci.
2010
, vol. 
123
 (pg. 
3071
-
3083
)
[PubMed]
29
Yu
J.
Pan
L.
Qin
X.
Chen
H.
Xu
Y.
Chen
Y.
Tang
H.
MTMR4 attenuates transforming growth factor β (TGFβ) signaling by dephosphorylating R-Smads in endosomes
J. Biol. Chem.
2010
, vol. 
285
 (pg. 
8454
-
8462
)
[PubMed]
30
Laporte
J.
Biancalana
V.
Tanner
S. M.
Kress
W.
Schneider
V.
Wallgren-Pettersson
C.
Herger
F.
Buj-Bello
A.
Blondeau
F.
Liechti-Gallati
S.
Mandel
J.-L.
MTM1 mutations in X-linked myotubular myopathy
Hum. Mutat.
2000
, vol. 
15
 (pg. 
393
-
409
)
[PubMed]
31
Royer
B.
Hnia
K.
Gavriilidis
C.
Tronchere
H.
Tosch
V.
Laporte
J.
The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies
EMBO Rep.
2013
, vol. 
14
 (pg. 
907
-
915
)
[PubMed]
32
Simons
M.
Trotter
J.
Wrapping it up: the cell biology of myelination
Curr. Opin. Neurobiol.
2007
, vol. 
17
 (pg. 
533
-
540
)
[PubMed]
33
Bolino
A.
Bolis
A.
Previtali
S. C.
Dina
G.
Bussini
S.
Dati
G.
Amadio
S.
Del Carro
U.
Mruk
D. D.
Feltri
M. L.
, et al. 
Disruption of Mtmr2 produces CMT4B1-like neuropathy with myelin outfolding and impaired spermatogenesis
J. Cell Biol.
2004
, vol. 
167
 (pg. 
711
-
721
)
[PubMed]
34
Bolino
A.
Muglia
M.
Conforti
F. L.
LeGuern
E.
Salih
M. A. M.
Georgiou
D. M.
Christodoulou
K.
Hausmanowa-Petrusewicz
I.
Mandich
P.
Schenone
A.
, et al. 
Charcot–Marie–Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2
Nat. Genet.
2000
, vol. 
25
 (pg. 
17
-
19
)
[PubMed]
35
Senderek
J.
Bergmann
C.
Weber
S.
Ketelsen
U.-P.
Schorle
H.
Rudnik-Schöneborn
S.
Büttner
R.
Buchheim
E.
Zerres
K.
Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot–Marie–Tooth neuropathy type 4B2/11p15
Hum. Mol. Genet.
2003
, vol. 
12
 (pg. 
349
-
356
)
[PubMed]
36
Chow
C. Y.
Zhang
Y.
Dowling
J. J.
Jin
N.
Adamska
M.
Shiga
K.
Szigeti
K.
Shy
M. E.
Li
J.
Zhang
X.
, et al. 
Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J
Nature
2007
, vol. 
448
 (pg. 
68
-
72
)
[PubMed]
37
Dall’Armi
C.
Devereaux
K. A.
Di Paolo
G.
The role of lipids in the control of autophagy
Curr. Biol.
2013
, vol. 
23
 (pg. 
R33
-
R45
)
[PubMed]
38
Vergne
I.
Deretic
V.
The role of PI3P phosphatases in the regulation of autophagy
FEBS Lett.
2010
, vol. 
584
 (pg. 
1313
-
1318
)
[PubMed]
39
Tosch
V.
Rohde
H. M.
Tronchère
H.
Zanoteli
E.
Monroy
N.
Kretz
C.
Dondaine
N.
Payrastre
B.
Mandel
J.-L.
Laporte
J.
A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
3098
-
3106
)
[PubMed]
40
Vergne
I.
Roberts
E.
Elmaoued
R. A.
Tosch
V.
Delgado
M. A.
Proikas-Cezanne
T.
Laporte
J.
Deretic
V.
Control of autophagy initiation by phosphoinositide 3-phosphatase jumpy
EMBO J.
2009
, vol. 
28
 (pg. 
2244
-
2258
)
[PubMed]
41
Cebollero
E.
van der Vaart
A.
Zhao
M.
Rieter
E.
Klionsky
D. J.
Helms
J. B.
Reggiori
F.
Phosphatidylinositol-3-phosphate clearance plays a key role in autophagosome completion
Curr. Biol.
2012
, vol. 
22
 (pg. 
1545
-
1553
)
[PubMed]
42
Song
M. S.
Salmena
L.
Pandolfi
P. P.
The functions and regulation of the PTEN tumour suppressor
Nat. Rev. Mol. Cell Biol.
2012
, vol. 
13
 (pg. 
283
-
296
)
[PubMed]
43
Martin-Belmonte
F.
Gassama
A.
Datta
A.
Yu
W.
Rescher
U.
Gerke
V.
Mostov
K.
PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42
Cell
2007
, vol. 
128
 (pg. 
383
-
397
)
[PubMed]
44
Kim
J. S.
Peng
X.
De
P. K.
Geahlen
R. L.
Durden
D. L.
PTEN controls immunoreceptor (immunoreceptor tyrosine-based activation motif) signaling and the activation of Rac
Blood
2002
, vol. 
99
 (pg. 
694
-
697
)
[PubMed]
45
Arico
S.
Petiot
A.
Bauvy
C.
Dubbelhuis
P. F.
Meijer
A. J.
Codogno
P.
Ogier-Denis
E.
The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
35243
-
35246
)
[PubMed]
46
Norris
F. A.
Majerus
P. W.
Hydrolysis of phosphatidylinositol 3,4-bisphosphate by inositol polyphosphate 4-phosphatase isolated by affinity elution chromatography
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
8716
-
8720
)
[PubMed]
47
Norris
F. A.
Atkins
R. C.
Majerus
P. W.
The cDNA cloning and characterization of inositol polyphosphate 4-phosphatase type II: evidence for conserved alternative splicing in the 4-phosphatase family
J. Biol. Chem.
1997
, vol. 
272
 (pg. 
23859
-
23864
)
[PubMed]
48
Ungewickell
A.
Hugge
C.
Kisseleva
M.
Chang
S.-C.
Zou
J.
Feng
Y.
Galyov
E. E.
Wilson
M.
Majerus
P. W.
The identification and characterization of two phosphatidylinositol-4,5-bisphosphate 4-phosphatases
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
18854
-
18859
)
[PubMed]
49
Rynkiewicz
N. K.
Liu
H.-J.
Balamatsias
D.
Mitchell
C. A.
INPP4A/INPP4B and P-Rex proteins: related but different?
Adv. Biol. Regul.
2012
, vol. 
52
 (pg. 
265
-
279
)
50
Ivetac
I.
Munday
A. D.
Kisseleva
M. V.
Zhang
X.-M.
Luff
S.
Tiganis
T.
Whisstock
J. C.
Rowe
T.
Majerus
P. W.
Mitchell
C. A.
The type Iα inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane
Mol. Biol. Cell
2005
, vol. 
16
 (pg. 
2218
-
2233
)
[PubMed]
51
Shin
H.-W.
Hayashi
M.
Christoforidis
S.
Lacas-Gervais
S.
Hoepfner
S.
Wenk
M. R.
Modregger
J.
Uttenweiler-Joseph
S.
Wilm
M.
Nystuen
A.
, et al. 
An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway
J. Cell Biol.
2005
, vol. 
170
 (pg. 
607
-
618
)
[PubMed]
52
Sasaki
J.
Kofuji
S.
Itoh
R.
Momiyama
T.
Takayama
K.
Murakami
H.
Chida
S.
Tsuya
Y.
Takasuga
S.
Eguchi
S.
, et al. 
The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death
Nature
2010
, vol. 
465
 (pg. 
497
-
501
)
[PubMed]
53
Nystuen
A.
Legare
M. E.
Shultz
L. D.
Frankel
W. N.
A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice
Neuron
2001
, vol. 
32
 (pg. 
203
-
212
)
[PubMed]
54
Sachs
A. J.
David
S. A.
Haider
N. B.
Nystuen
A. M.
Patterned neuroprotection in the Inpp4awbl mutant mouse cerebellum correlates with the expression of Eaat4
PLoS ONE
2009
, vol. 
4
 pg. 
e8270
 
[PubMed]
55
Karayiorgou
M.
Simon
T. J.
Gogos
J. A.
22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia
Nat. Rev. Neurosci.
2010
, vol. 
11
 (pg. 
402
-
416
)
[PubMed]
56
Wang
L.
Luo
J.
Fang
M.
Jiang
G.
Zhang
X.
Yu
W.
Wang
X.
A new trick of INPP4A: decreased expression of INPP4A in patients with temporal lobe epilepsy and pilocarpine-induced rat model
Synapse
2012
, vol. 
66
 (pg. 
533
-
541
)
[PubMed]
57
Ivetac
I.
Gurung
R.
Hakim
S.
Horan
K. A.
Sheffield
D. A.
Binge
L. C.
Majerus
P. W.
Tiganis
T.
Mitchell
C. A.
Regulation of PI(3)K/Akt signalling and cellular transformation by inositol polyphosphate 4-phosphatase-1
EMBO Rep.
2009
, vol. 
10
 (pg. 
487
-
493
)
[PubMed]
58
Sharma
M.
Batra
J.
Mabalirajan
U.
Sharma
S.
Nagarkatti
R.
Aich
J.
Sharma
S. K.
Niphadkar
P. V.
Ghosh
B.
A genetic variation in inositol polyphosphate 4 phosphatase A enhances susceptibility to asthma
Am. J. Respir. Crit. Care Med.
2008
, vol. 
177
 (pg. 
712
-
719
)
[PubMed]
59
Ferron
M.
Vacher
J.
Characterization of the murine Inpp4b gene and identification of a novel isoform
Gene
2006
, vol. 
376
 (pg. 
152
-
161
)
[PubMed]
60
Bertucci
M. C.
Mitchell
C. A.
Phosphoinositide 3-kinase and INPP4B in human breast cancer
Ann. N.Y. Acad. Sci.
2013
, vol. 
1280
 (pg. 
1
-
5
)
[PubMed]
61
Ferron
M.
Boudiffa
M.
Arsenault
M.
Rached
M.
Pata
M.
Giroux
S.
Elfassihi
L.
Kisseleva
M.
Majerus
P. W.
Rousseau
F.
Vacher
J.
Inositol polyphosphate 4-phosphatase B as a regulator of bone mass in mice and humans
Cell Metab.
2011
, vol. 
14
 (pg. 
466
-
477
)
[PubMed]
62
Guo
S.
Stolz
L. E.
Lemrow
S. M.
York
J. D.
SAC1-like domains of yeast SAC1,INP52, and INP53 and of human synaptojanin encode polyphosphoinositide phosphatases
J. Biol. Chem.
1999
, vol. 
274
 (pg. 
12990
-
12995
)
[PubMed]
63
Attree
O.
Olivos
I. M.
Okabe
I.
Bailey
L. C.
Nelson
D. L.
Lewis
R. A.
McLnnes
R. R.
Nussbaum
R. L.
The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase
Nature
1992
, vol. 
358
 (pg. 
239
-
242
)
[PubMed]
64
Hoopes
R. R.
Jr
Shrimpton
A. E.
Knohl
S. J.
Hueber
P.
Hoppe
B.
Matyus
J.
Simckes
A.
Tasic
V.
Toenshoff
B.
Suchy
S. F.
, et al. 
Dent disease with mutations in OCRL1
Am. J. Hum. Genet.
2005
, vol. 
76
 (pg. 
260
-
267
)
[PubMed]
65
Jänne
P. A.
Suchy
S. F.
Bernard
D.
MacDonald
M.
Crawley
J.
Grinberg
A.
Wynshaw-Boris
A.
Westphal
H.
Nussbaum
R. L.
Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice
J. Clin. Invest.
1998
, vol. 
101
 (pg. 
2042
-
2053
)
[PubMed]
66
Schroer
R. J.
Beaudet
A. L.
Shinawi
M.
Sahoo
T.
Patel
A.
Sun
Q.
Skinner
C.
Stevenson
R. E.
Duplication of OCRL and adjacent genes associated with autism but not Lowe syndrome
Am. J. Med. Genet. A.
2012
, vol. 
158A
 (pg. 
2602
-
2605
)
[PubMed]
67
Pirruccello
M.
De Camilli
P.
Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL
Trends Biochem. Sci.
2012
, vol. 
37
 (pg. 
134
-
143
)
[PubMed]
68
Mehta
Z. B.
Pietka
G.
Lowe
M.
The cellular and physiological functions of the Lowe syndrome protein OCRL1
Traffic
2014
, vol. 
15
 (pg. 
471
-
487
)
[PubMed]
69
Schmid
A. C.
Wise
H. M.
Mitchell
C. A.
Nussbaum
R.
Woscholski
R.
Type II phosphoinositide 5-phosphatases have unique sensitivities towards fatty acid composition and head group phosphorylation
FEBS Lett.
2004
, vol. 
576
 (pg. 
9
-
13
)
[PubMed]
70
Choudhury
R.
Diao
A.
Zhang
F.
Eisenberg
E.
Saint-Pol
A.
Williams
C.
Konstantakopoulos
A.
Lucocq
J.
Johannes
L.
Rabouille
C.
, et al. 
Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network
Mol. Biol. Cell
2005
, vol. 
16
 (pg. 
3467
-
3479
)
[PubMed]
71
Vicinanza
M.
Di Campli
A.
Polishchuk
E.
Santoro
M.
Di Tullio
G.
Godi
A.
Levtchenko
E.
De Leo
M. G.
Polishchuk
R.
Sandoval
L.
, et al. 
OCRL controls trafficking through early endosomes via PtdIns4,5P2-dependent regulation of endosomal actin
EMBO J.
2011
, vol. 
30
 (pg. 
4970
-
4985
)
[PubMed]
72
van Rahden
V. A.
Brand
K.
Najm
J.
Heeren
J.
Pfeffer
S. R.
Braulke
T.
Kutsche
K.
The 5-phosphatase OCRL mediates retrograde transport of the mannose 6-phosphate receptor by regulating a Rac1–cofilin signalling module
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
5019
-
5038
)
[PubMed]
73
Rodriguez-Gabin
A. G.
Ortiz
E.
Demoliner
K.
Si
Q.
Almazan
G.
Larocca
J. N.
Interaction of Rab31 and OCRL-1 in oligodendrocytes: its role in transport of mannose 6-phosphate receptors
J. Neurosci. Res.
2010
, vol. 
88
 (pg. 
589
-
604
)
[PubMed]
74
Wenk
M. R.
Lucast
L.
Di Paolo
G.
Romanelli
A. J.
Suchy
S. F.
Nussbaum
R. L.
Cline
G. W.
Shulman
G. I.
McMurray
W.
De Camilli
P.
Phosphoinositide profiling in complex lipid mixtures using electrospray ionization mass spectrometry
Nat. Biotechnol.
2003
, vol. 
21
 (pg. 
813
-
817
)
[PubMed]
75
Ramirez
I. B.-R.
Pietka
G.
Jones
D. R.
Divecha
N.
Alia
A.
Baraban
S. C.
Hurlstone
A. F. L.
Lowe
M.
Impaired neural development in a zebrafish model for Lowe syndrome
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
1744
-
1759
)
[PubMed]
76
Loovers
H. M.
Kortholt
A.
de Groote
H.
Whitty
L.
Nussbaum
R. L.
van Haastert
P. J. M.
Regulation of phagocytosis in Dictyostelium by the inositol 5-phosphatase OCRL homolog Dd5P4
Traffic
2007
, vol. 
8
 (pg. 
618
-
628
)
[PubMed]
77
Dambournet
D.
Machicoane
M.
Chesneau
L.
Sachse
M.
Rocancourt
M.
El Marjou
A.
Formstecher
E.
Salomon
R.
Goud
B.
Echard
A.
Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis
Nat. Cell Biol.
2011
, vol. 
13
 (pg. 
981
-
988
)
[PubMed]
78
Ben El Kadhi
K.
Roubinet
C.
Solinet
S.
Eméry
G.
Carréno
S.
The Inositol 5-phosphatase dOCRL controls PI(4,5)P2 homeostasis and is necessary for cytokinesis
Curr. Biol.
2011
, vol. 
21
 (pg. 
1074
-
1079
)
[PubMed]
79
Grieve
A. G.
Daniels
R. D.
Sanchez-Heras
E.
Hayes
M. J.
Moss
S. E.
Matter
K.
Lowe
M.
Levine
T. P.
Lowe syndrome protein OCRL1 supports maturation of polarized epithelial cells
PLoS ONE
2011
, vol. 
6
 pg. 
e24044
 
[PubMed]
80
Coon
B. G.
Hernandez
V.
Madhivanan
K.
Mukherjee
D.
Hanna
C. B.
Barinaga-Rementeria Ramirez
I.
Lowe
M.
Beales
P. L.
Aguilar
R. C.
The Lowe syndrome protein OCRL1 is involved in primary cilia assembly
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
1835
-
1847
)
[PubMed]
81
Rbaibi
Y.
Cui
S.
Mo
D.
Carattino
M.
Rohatgi
R.
Satlin
L. M.
Szalinski
C. M.
Swanhart
L. M.
Fölsch
H.
Hukriede
N. A.
Weisz
O. A.
OCRL1 modulates cilia length in renal epithelial cells
Traffic
2012
, vol. 
13
 (pg. 
1295
-
1305
)
[PubMed]
82
Jackson
S. P.
Schoenwaelder
S. M.
Matzaris
M.
Brown
S.
Mitchell
C. A.
Phosphatidylinositol 3,4,5-trisphosphate is a substrate for the 75-kDa inositol polyphosphate 5-phosphatase and a novel 5-phosphatase which forms a complex with the p85/p110 form of phosphoinositide 3-kinase
EMBO J.
1995
, vol. 
14
 (pg. 
4490
-
4500
)
[PubMed]
83
Matzaris
M.
Jackson
S. P.
Laxminarayan
K. M.
Speed
C. J.
Mitchell
C. A.
Identification and characterization of the phosphatidylinositol-(4, 5)-bisphosphate 5-phosphatase in human platelets
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
3397
-
3402
)
[PubMed]
84
Williams
C.
Choudhury
R.
McKenzie
E.
Lowe
M.
Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway
J. Cell Sci.
2007
, vol. 
120
 (pg. 
3941
-
3951
)
[PubMed]
85
Erdmann
K. S.
Mao
Y.
McCrea
H. J.
Zoncu
R.
Lee
S.
Paradise
S.
Modregger
J.
Biemesderfer
D.
Toomre
D.
De Camilli
P.
A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway
Dev. Cell
2007
, vol. 
13
 (pg. 
377
-
390
)
[PubMed]
86
Bohdanowicz
M.
Balkin
D. M.
De Camilli
P.
Grinstein
S.
Recruitment of OCRL and Inpp5B to phagosomes by Rab5 and APPL1 depletes phosphoinositides and attenuates Akt signaling
Mol. Biol. Cell
2012
, vol. 
23
 (pg. 
176
-
187
)
[PubMed]
87
Bohdanowicz
M.
Cosío
G.
Backer
J. M.
Grinstein
S.
Class I and class III phosphoinositide 3-kinases are required for actin polymerization that propels phagosomes
J. Cell Biol.
2010
, vol. 
191
 (pg. 
999
-
1012
)
[PubMed]
88
Luo
N.
Kumar
A.
Conwell
M.
Weinreb
R. N.
Anderson
R.
Sun
Y.
Compensatory role of inositol 5-phosphatase INPP5B to OCRL in primary cilia formation in oculocerebrorenal syndrome of Lowe
PLoS ONE
2013
, vol. 
8
 pg. 
e66727
 
[PubMed]
89
Hellsten
E.
Bernard
D. J.
Owens
J. W.
Eckhaus
M.
Suchy
S. F.
Nussbaum
R. L.
Sertoli cell vacuolization and abnormal germ cell adhesion in mice deficient in an inositol polyphosphate 5-phosphatase
Biol. Reprod.
2002
, vol. 
66
 (pg. 
1522
-
1530
)
[PubMed]
90
Nemoto
Y.
Arribas
M.
Haffner
C.
DeCamilli
P.
Synaptojanin 2, a novel synaptojanin isoform with a distinct targeting domain and expression pattern
J. Biol. Chem.
1997
, vol. 
272
 (pg. 
30817
-
30821
)
[PubMed]
91
Ramjaun
A. R.
McPherson
P. S.
Tissue-specific alternative splicing generates two synaptojanin isoforms with differential membrane binding properties
J. Biol. Chem.
1996
, vol. 
271
 (pg. 
24856
-
24861
)
[PubMed]
92
Nemoto
Y.
Wenk
M. R.
Watanabe
M.
Daniell
L.
Murakami
T.
Ringstad
N.
Yamada
H.
Takei
K.
De Camilli
P.
Identification and characterization of a synaptojanin 2 splice isoform predominantly expressed in nerve terminals
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
41133
-
41142
)
[PubMed]
93
Seet
L.-F.
Cho
S.
Hessel
A.
Dumont
D. J.
Molecular cloning of multiple isoforms of synaptojanin 2 and assignment of the gene to mouse chromosome 17A2-3.1
Biochem. Biophys. Res. Commun.
1998
, vol. 
247
 (pg. 
116
-
122
)
[PubMed]
94
McPherson
P. S.
Garcia
E. P.
Slepnev
V. I.
David
C.
Zhang
X.
Grabs
D.
Sossini
W. S.
Bauerfeind
R.
Nemoto
Y.
De Camilli
P.
A presynaptic inositol-5-phosphatase
Nature
1996
, vol. 
379
 (pg. 
353
-
357
)
[PubMed]
95
Perera
R. M.
Zoncu
R.
Lucast
L.
De Camilli
P.
Toomre
D.
Two synaptojanin 1 isoforms are recruited to clathrin-coated pits at different stages
Proc. Natl. Acad. Sci. U.S.A.
2006
, vol. 
103
 (pg. 
19332
-
19337
)
[PubMed]
96
Cremona
O.
Di Paolo
G.
Wenk
M. R.
Lüthi
A.
Kim
W. T.
Takei
K.
Daniell
L.
Nemoto
Y.
Shears
S. B.
Flavell
R. A.
, et al. 
Essential role of phosphoinositide metabolism in synaptic vesicle recycling
Cell
1999
, vol. 
99
 (pg. 
179
-
188
)
[PubMed]
97
Harris
T. W.
Hartwieg
E.
Horvitz
H. R.
Jorgensen
E. M.
Mutations in synaptojanin disrupt synaptic vesicle recycling
J. Cell Biol.
2000
, vol. 
150
 (pg. 
589
-
600
)
[PubMed]
98
Mani
M.
Lee
S. Y.
Lucast
L.
Cremona
O.
Di Paolo
G.
De Camilli
P.
Ryan
T. A.
The dual phosphatase activity of synaptojanin1 is required for both efficient synaptic vesicle endocytosis and reavailability at nerve terminals
Neuron
2007
, vol. 
56
 (pg. 
1004
-
1018
)
[PubMed]
99
Arai
Y.
Ijuin
T.
Takenawa
T.
Becker
L. E.
Takashima
S.
Excessive expression of synaptojanin in brains with Down syndrome
Brain Dev.
2002
, vol. 
24
 (pg. 
67
-
72
)
[PubMed]
100
Cossec
J.-C.
Lavaur
J.
Berman
D. E.
Rivals
I.
Hoischen
A.
Stora
S.
Ripoll
C.
Mircher
C.
Grattau
Y.
OlivoMarin
J.-C.
, et al. 
Trisomy for synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
3156
-
3172
)
[PubMed]
101
Berman
D. E.
Dall’Armi
C.
Voronov
S. V.
McIntire
L. B. J.
Zhang
H.
Moore
A. Z.
Staniszewski
A.
Arancio
O.
Kim
T.-W.
Di Paolo
G.
Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
Nat. Neurosci.
2008
, vol. 
11
 (pg. 
547
-
554
)
[PubMed]
102
McIntire
L. B. J.
Berman
D. E.
Myaeng
J.
Staniszewski
A.
Arancio
O.
Di Paolo
G.
Kim
T.-W.
Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease
J. Neurosci.
2012
, vol. 
32
 (pg. 
15271
-
15276
)
[PubMed]
103
Zhu
L.
Zhong
M.
Zhao
J.
Rhee
H.
Caesar
I.
Knight
E.
Volpicelli-Daley
L.
Bustos
V.
Netzer
W.
Liu
L.
, et al. 
Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model
J. Biol. Chem.
2013
, vol. 
288
 (pg. 
32050
-
32063
)
[PubMed]
104
Krebs
C. E.
Karkheiran
S.
Powell
J. C.
Cao
M.
Makarov
V.
Darvish
H.
Di Paolo
G.
Walker
R. H.
Shahidi
G. A.
Buxbaum
J. D.
, et al. 
The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures
Hum. Mutat.
2013
, vol. 
34
 (pg. 
1200
-
1207
)
[PubMed]
105
Rusk
N.
Le
P. U.
Mariggio
S.
Guay
G.
Lurisci
C.
Nabi
I. R.
Corda
D.
Symons
M.
Synaptojanin 2 functions at an early step of clathrin-mediated endocytosis
Curr. Biol.
2003
, vol. 
13
 (pg. 
659
-
663
)
[PubMed]
106
Malecz
N.
McCabe
P. C.
Spaargaren
C.
Qiu
R.-G.
Chuang
Y.-y.
Symons
M.
Synaptojanin 2, a novel Rac1 effector that regulates clathrin-mediated endocytosis
Curr. Biol.
2000
, vol. 
10
 (pg. 
1383
-
1386
)
[PubMed]
107
Manji
S. S. M.
Williams
L. H.
Miller
K. A.
Ooms
L. M.
Bahlo
M.
Mitchell
C. A.
Dahl
H.-H. M.
A mutation in synaptojanin 2 causes progressive hearing loss in the ENU-mutagenised mouse strain Mozart
PLoS ONE
2011
, vol. 
6
 pg. 
e17607
 
[PubMed]
108
Kong
A. M.
Speed
C. J.
O’Malley
C. J.
Layton
M. J.
Meehan
T.
Loveland
K. L.
Cheema
S.
Ooms
L. M.
Mitchell
C. A.
Cloning and characterization of a 72-kDa inositol-polyphosphate 5-phosphatase localized to the Golgi network
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
24052
-
24064
)
[PubMed]
109
Kisseleva
M. V.
Wilson
M. P.
Majerus
P. W.
The isolation and characterization of a cDNA encoding phospholipid-specific inositol polyphosphate 5-phosphatase
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
20110
-
20116
)
[PubMed]
110
Kong
A. M.
Horan
K. A.
Sriratana
A.
Bailey
C. G.
Collyer
L. J.
Nandurkar
H. H.
Shisheva
A.
Layton
M. J.
Rasko
J. E. J.
Rowe
T.
Mitchell
C. A.
Phosphatidylinositol 3-phosphate [PtdIns(3)P] is generated at the plasma membrane by an inositol polyphosphate 5-phosphatase: endogenous PtdIns(3)P can promote GLUT4 translocation to the plasma membrane
Mol. Cell. Biol.
2006
, vol. 
26
 (pg. 
6065
-
6081
)
[PubMed]
111
Jacoby
M.
Cox
J. J.
Gayral
S.
Hampshire
D. J.
Ayub
M.
Blockmans
M.
Pernot
E.
Kisseleva
M. V.
Compere
P.
Schiffmann
S. N.
, et al. 
INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse
Nat. Genet.
2009
, vol. 
41
 (pg. 
1027
-
1031
)
[PubMed]
112
Bielas
S. L.
Silhavy
J. L.
Brancati
F.
Kisseleva
M. V.
Al-Gazali
L.
Sztriha
L.
Bayoumi
R. A.
Zaki
M. S.
Abdel-Aleem
A.
Rosti
R. O.
, et al. 
Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies
Nat. Genet.
2009
, vol. 
41
 (pg. 
1032
-
1036
)
[PubMed]
113
Horan
K. A.
Watanabe
K.-i.
Kong
A. M.
Bailey
C. G.
Rasko
J. E. J.
Sasaki
T.
Mitchell
C. A.
Regulation of FcγR-stimulated phagocytosis by the 72-kDa inositol polyphosphate 5-phosphatase: SHIP1, but not the 72-kDa 5-phosphatase, regulates complement receptor 3-mediated phagocytosis by differential recruitment of these 5-phosphatases to the phagocytic cup
Blood
2007
, vol. 
110
 (pg. 
4480
-
4491
)
[PubMed]
114
Luo
N.
Lu
J.
Sun
Y.
Evidence of a role of inositol polyphosphate 5-phosphatase INPP5E in cilia formation in zebrafish
Vision Res.
2012
, vol. 
75
 (pg. 
98
-
107
)
[PubMed]
115
Pesesse
X.
Deleu
S.
De Smedt
F.
Drayer
L.
Erneux
C.
Identification of a second SH2-domain-containing protein closely related to the phosphatidylinositol polyphosphate 5-phosphatase SHIP
Biochem. Biophys. Res. Commun.
1997
, vol. 
239
 (pg. 
697
-
700
)
[PubMed]
116
Liu
Q.
Shalaby
F.
Jones
J.
Bouchard
D.
Dumont
D. J.
The SH2-containing inositol polyphosphate 5-phosphatase, SHIP, is expressed during hematopoiesis and spermatogenesis
Blood
1998
, vol. 
91
 (pg. 
2753
-
2759
)
[PubMed]
117
Bai
L.
Rohrschneider
L. R.
s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue
Genes Dev.
2010
, vol. 
24
 (pg. 
1882
-
1892
)
[PubMed]
118
Hamilton
M. J.
Ho
V. W.
Kuroda
E.
Ruschmann
J.
Antignano
F.
Lam
V.
Krystal
G.
Role of SHIP in cancer
Exp. Hematol.
2011
, vol. 
39
 (pg. 
2
-
13
)
[PubMed]
119
Kamen
L. A.
Levinsohn
J.
Swanson
J. A.
Differential association of phosphatidylinositol 3-kinase, SHIP-1, and PTEN with forming phagosomes
Mol. Biol. Cell
2007
, vol. 
18
 (pg. 
2463
-
2472
)
[PubMed]
120
Muraille
E.
Dassesse
D.
Vanderwinden
J. M.
Cremer
H.
Rogister
B.
Erneux
C.
Schiffmann
S. N.
The SH2 domain-containing 5-phosphatase SHIP2 is expressed in the germinal layers of embryo and adult mouse brain: increased expression in N-CAM-deficient mice
Neuroscience
2001
, vol. 
105
 (pg. 
1019
-
1030
)
[PubMed]
121
Taylor
V.
Wong
M.
Brandts
C.
Reilly
L.
Dean
N. M.
Cowsert
L. M.
Moodie
S.
Stokoe
D.
5′ phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells
Mol. Cell. Biol.
2000
, vol. 
20
 (pg. 
6860
-
6871
)
[PubMed]
122
Chi
Y.
Zhou
B.
Wang
W.-Q.
Chung
S.-K.
Kwon
Y.-U.
Ahn
Y.-H.
Chang
Y.-T.
Tsujishita
Y.
Hurley
J. H.
Zhang
Z.-Y.
Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe synaptojanin and SHIP2
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
44987
-
44995
)
[PubMed]
123
Nakatsu
F.
Perera
R. M.
Lucast
L.
Zoncu
R.
Domin
J.
Gertler
F. B.
Toomre
D.
De Camilli
P.
The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics
J. Cell Biol.
2010
, vol. 
190
 (pg. 
307
-
315
)
[PubMed]
124
Prasad
N.
Topping
R. S.
Decker
S. J.
SH2-containing inositol 5-phosphatase SHIP2 associates with the p130Cas adapter protein and regulates cellular adhesion and spreading
Mol. Cell. Biol.
2001
, vol. 
21
 (pg. 
1416
-
1428
)
[PubMed]
125
Dyson
J. M.
O’Malley
C. J.
Becanovic
J.
Munday
A. D.
Berndt
M. C.
Coghill
I. D.
Nandurkar
H. H.
Ooms
L. M.
Mitchell
C. A.
The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin
J. Cell Biol.
2001
, vol. 
155
 (pg. 
1065
-
1080
)
[PubMed]
126
Kato
K.
Yazawa
T.
Taki
K.
Mori
K.
Wang
S.
Nishioka
T.
Hamaguchi
T.
Itoh
T.
Takenawa
T.
Kataoka
C.
, et al. 
The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration
Mol. Biol. Cell
2012
, vol. 
23
 (pg. 
2593
-
2604
)
[PubMed]
127
Prasad
N. K.
SHIP2 phosphoinositol phosphatase positively regulates EGFR–Akt pathway, CXCR4 expression, and cell migration in MDA-MB-231 breast cancer cells
Int. J. Oncol.
2009
, vol. 
34
 (pg. 
97
-
105
)
[PubMed]
128
Prasad
N. K.
Decker
S. J.
SH2-containing 5′-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor
J. Biol. Chem.
2005
, vol. 
280
 (pg. 
13129
-
13136
)
[PubMed]
129
Zhuang
G.
Hunter
S.
Hwang
Y.
Chen
J.
Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-kinase-dependent Rac1 activation
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
2683
-
2694
)
[PubMed]
130
Ai
J.
Maturu
A.
Johnson
W.
Wang
Y.
Marsh
C. B.
Tridandapani
S.
The inositol phosphatase SHIP-2 down-regulates FcγR-mediated phagocytosis in murine macrophages independently of SHIP-1
Blood
2006
, vol. 
107
 (pg. 
813
-
820
)
[PubMed]
131
Sleeman
M. W.
Wortley
K. E.
Lai
K.-M. V.
Gowen
L. C.
Kintner
J.
Kline
W. O.
Garcia
K.
Stitt
T. N.
Yancopoulos
G. D.
Wiegand
S. J.
Glass
D. J.
Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity
Nat. Med.
2005
, vol. 
11
 (pg. 
199
-
205
)
[PubMed]
132
Suwa
A.
Kurama
T.
Shimokawa
T.
SHIP2 and its involvement in various diseases
Expert Opin. Ther. Targets
2010
, vol. 
14
 (pg. 
727
-
737
)
[PubMed]
133
Ijuin
T.
Mochizuki
Y.
Fukami
K.
Funaki
M.
Asano
T.
Takenawa
T.
Identification and characterization of a novel inositol polyphosphate 5-phosphatase
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
10870
-
10875
)
[PubMed]
134
Gurung
R.
Tan
A.
Ooms
L. M.
McGrath
M. J.
Huysmans
R. D.
Munday
A. D.
Prescott
M.
Whisstock
J. C.
Mitchell
C. A.
Identification of a novel domain in two mammalian inositol-polyphosphate 5-phosphatases that mediates membrane ruffle localization: the inositol 5-phosphatase SKIP localizes to the endoplasmic reticulum and translocates to membrane ruffles following epidermal growth factor stimulation
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
11376
-
11385
)
[PubMed]
135
Ijuin
T.
Takenawa
T.
SKIP Negatively regulates insulin-induced GLUT4 translocation and membrane ruffle formation
Mol. Cell. Biol.
2003
, vol. 
23
 (pg. 
1209
-
1220
)
[PubMed]
136
Mochizuki
Y.
Takenawa
T.
Novel inositol polyphosphate 5-phosphatase localizes at membrane ruffles
J. Biol. Chem.
1999
, vol. 
274
 (pg. 
36790
-
36795
)
[PubMed]
137
Ooms
L. M.
Fedele
C. G.
Astle
M. V.
Ivetac
I.
Cheung
V.
Pearson
R. B.
Layton
M. J.
Forrai
A.
Nandurkar
H. H.
Mitchell
C. A.
The inositol polyphosphate 5-phosphatase, PIPP, is a novel regulator of phosphoinositide 3-kinase-dependent neurite elongation
Mol. Biol. Cell
2006
, vol. 
17
 (pg. 
607
-
622
)
[PubMed]
138
Denley
A.
Gymnopoulos
M.
Kang
S.
Mitchell
C.
Vogt
P. K.
Requirement of phosphatidylinositol(3,4,5)trisphosphate in phosphatidylinositol 3-kinase-induced oncogenic transformation
Mol. Cancer Res.
2009
, vol. 
7
 (pg. 
1132
-
1138
)
[PubMed]
139
Laxminarayan
K. M.
Matzaris
M.
Speed
C. J.
Mitchell
C. A.
Purification and characterization of a 43-kDa membrane-associated inositol polyphosphate 5-phosphatase from human placenta
J. Biol. Chem.
1993
, vol. 
268
 (pg. 
4968
-
4974
)
[PubMed]
140
Speed
C. J.
Neylon
C. B.
Little
P. J.
Mitchell
C. A.
Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with spontaneous calcium oscillations and enhanced calcium responses following endothelin-1 stimulation
J. Cell Sci.
1999
, vol. 
112
 (pg. 
669
-
679
)
[PubMed]
141
Windhorst
S.
Minge
D.
Bähring
R.
Huüser
S.
Schob
C.
Blechner
C.
Lin
H.-Y.
Mayr
G. W.
Kindler
S.
Inositol-1,4,5-trisphosphate 3-kinase A regulates dendritic morphology and shapes synaptic Ca2+ transients
Cell. Signall.
2012
, vol. 
24
 (pg. 
750
-
757
)
142
Kasumu
A. W.
Liang
X.
Egorova
P.
Vorontsova
D.
Bezprozvanny
I.
Chronic suppression of inositol 1,4,5-triphosphate receptor-mediated calcium signaling in cerebellar Purkinje cells alleviates pathological phenotype in spinocerebellar ataxia 2 mice
J. Neurosci.
2012
, vol. 
32
 (pg. 
12786
-
12796
)
[PubMed]
143
Konrad
G.
Schlecker
T.
Faulhammer
F.
Mayinger
P.
Retention of the yeast Sac1p phosphatase in the endoplasmic reticulum causes distinct changes in cellular phosphoinositide levels and stimulates microsomal ATP transport
J. Biol. Chem.
2002
, vol. 
277
 (pg. 
10547
-
10554
)
[PubMed]
144
Nemoto
Y.
Kearns
B. G.
Wenk
M. R.
Chen
H.
Mori
K.
Alb
J. G.
De Camilli
P.
Bankaitis
V. A.
Functional characterization of a mammalian sac1 and mutants exhibiting substrate-specific defects in phosphoinositide phosphatase activity
J. Biol. Chem.
2000
, vol. 
275
 (pg. 
34293
-
34305
)
[PubMed]
145
Whitters
E.
Cleves
A.
McGee
T.
Skinner
H.
Bankaitis
V.
SAC1p is an integral membrane protein that influences the cellular requirement for phospholipid transfer protein function and inositol in yeast
J. Cell Biol.
1993
, vol. 
122
 (pg. 
79
-
94
)
[PubMed]
146
Blagoveshchenskaya
A.
Cheong
F. Y.
Rohde
H. M.
Glover
G.
Knödler
A.
Nicolson
T.
Boehmelt
G.
Mayinger
P.
Integration of Golgi trafficking and growth factor signaling by the lipid phosphatase SAC1
J. Cell Biol.
2008
, vol. 
180
 (pg. 
803
-
812
)
[PubMed]
147
Schorr
M.
Then
A.
Tahirovic
S.
Hug
N.
Mayinger
P.
The phosphoinositide phosphatase Sac1p controls trafficking of the yeast Chs3p chitin synthase
Curr. Biol.
2001
, vol. 
11
 (pg. 
1421
-
1426
)
[PubMed]
148
Cheong
F. Y.
Sharma
V.
Blagoveshchenskaya
A.
Oorschot
V. M. J.
Brankatschk
B.
Klumperman
J.
Freeze
H. H.
Mayinger
P.
Spatial regulation of Golgi phosphatidylinositol-4-phosphate is required for enzyme localization and glycosylation fidelity
Traffic
2010
, vol. 
11
 (pg. 
1180
-
1190
)
[PubMed]
149
Liu
Y.
Boukhelifa
M.
Tribble
E.
Morin-Kensicki
E.
Uetrecht
A.
Bear
J. E.
Bankaitis
V. A.
The Sac1 phosphoinositide phosphatase regulates Golgi membrane morphology and mitotic spindle organization in mammals
Mol. Biol. Cell
2008
, vol. 
19
 (pg. 
3080
-
3096
)
[PubMed]
150
Forrest
S.
Chai
A.
Sanhueza
M.
Marescotti
M.
Parry
K.
Georgiev
A.
Sahota
V.
Mendez-Castro
R.
Pennetta
G.
Increased levels of phosphoinositides cause neurodegeneration in a Drosophila model of amyotrophic lateral sclerosis
Hum. Mol. Genet.
2013
, vol. 
22
 (pg. 
2689
-
2704
)
[PubMed]
151
Zhang
L.
Hong
Z.
Lin
W.
Shao
R.-X.
Goto
K.
Hsu
V. W.
Chung
R. T.
ARF1 and GBF1 generate a PI4P-enriched environment supportive of hepatitis C virus replication
PLoS ONE
2012
, vol. 
7
 pg. 
e32135
 
[PubMed]
152
Minagawa
T.
Ijuin
T.
Mochizuki
Y.
Takenawa
T.
Identification and characterization of a Sac domain-containing phosphoinositide 5-phosphatase
J. Biol. Chem.
2001
, vol. 
276
 (pg. 
22011
-
22015
)
[PubMed]
153
Zhu
W.
Trivedi
C. M.
Zhou
D.
Yuan
L.
Lu
M. M.
Epstein
J. A.
Inpp5f is a polyphosphoinositide phosphatase that regulates cardiac hypertrophic responsiveness
Circ. Res.
2009
, vol. 
105
 (pg. 
1240
-
1247
)
[PubMed]
154
Sbrissa
D.
Ikonomov
O. C.
Fu
Z.
Ijuin
T.
Gruenberg
J.
Takenawa
T.
Shisheva
A.
Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport: novel Sac phosphatase joins the ArPIKfyve–PIKfyve complex
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
23878
-
23891
)
[PubMed]
155
Yuan
Y.
Gao
X.
Guo
N.
Zhang
H.
Xie
Z.
Jin
M.
Li
B.
Yu
L.
Jing
N.
rSac3, a novel Sac domain phosphoinositide phosphatase, promotes neurite outgrowth in PC12 cells
Cell Res.
2007
, vol. 
17
 (pg. 
919
-
932
)
[PubMed]
156
Duex
J. E.
Nau
J. J.
Kauffman
E. J.
Weisman
L. S.
Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels
Eukaryot. Cell
2006
, vol. 
5
 (pg. 
723
-
731
)
[PubMed]
157
de Lartigue
J.
Polson
H.
Feldman
M.
Shokat
K.
Tooze
S. A.
Urbé
S.
Clague
M. J.
PIKfyve regulation of endosome-linked pathways
Traffic
2009
, vol. 
10
 (pg. 
883
-
893
)
[PubMed]
158
Ferguson
C. J.
Lenk
G. M.
Meisler
M. H.
Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2
Hum. Mol. Genet.
2009
, vol. 
18
 (pg. 
4868
-
4878
)
[PubMed]
159
Martyn
C.
Li
J.
Fig4 deficiency: a newly emerged lysosomal storage disorder?
Prog. Neurobiol.
2013
, vol. 
101–102
 (pg. 
35
-
45
)
160
Ferguson
C. J.
Lenk
G. M.
Jones
J. M.
Grant
A. E.
Winters
J. J.
Dowling
J. J.
Giger
R. J.
Meisler
M. H.
Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration
Hum. Mol. Genet.
2012
, vol. 
21
 (pg. 
3525
-
3534
)
[PubMed]
161
Zhang
X.
Chow
C. Y.
Sahenk
Z.
Shy
M. E.
Meisler
M. H.
Li
J.
Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration
Brain
2008
, vol. 
131
 (pg. 
1990
-
2001
)
[PubMed]
162
Lenk
G. M.
Ferguson
C. J.
Chow
C. Y.
Jin
N.
Jones
J. M.
Grant
A. E.
Zolov
S. N.
Winters
J. J.
Giger
R. J.
Dowling
J. J.
, et al. 
Pathogenic mechanism of the FIG4 mutation responsible for Charcot–Marie–Tooth disease CMT4J
PLoS Genet.
2011
, vol. 
7
 pg. 
e1002104
 
[PubMed]
163
Chow
C. Y.
Landers
J. E.
Bergren
S. K.
Sapp
P. C.
Grant
A. E.
Jones
J. M.
Everett
L.
Lenk
G. M.
McKenna-Yasek
D. M.
Weisman
L. S.
, et al. 
Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS
Am. J. Hum. Genet.
2009
, vol. 
84
 (pg. 
85
-
88
)
[PubMed]
164
Campeau
P. M.
Lenk
G. M.
Lu
J. T.
Bae
Y.
Burrage
L.
Turnpenny
P.
Corona-Rivera
J. R.
Morandi
L.
Mora
M.
Reutter
H.
, et al. 
Yunis–Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase
Am. J. Hum. Genet.
2013
, vol. 
92
 (pg. 
781
-
791
)
[PubMed]
165
Kon
T.
Mori
F.
Tanji
K.
Miki
Y.
Toyoshima
Y.
Yoshida
M.
Sasaki
H.
Kakita
A.
Takahashi
H.
Wakabayashi
K.
ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases
Neuropathology
2013
, vol. 
34
 (pg. 
19
-
26
)
[PubMed]
166
Weber
S. S.
Ragaz
C.
Hilbi
H.
Pathogen trafficking pathways and host phosphoinositide metabolism
Mol. Microbiol.
2009
, vol. 
71
 (pg. 
1341
-
1352
)
[PubMed]
167
Ham
H.
Sreelatha
A.
Orth
K.
Manipulation of host membranes by bacterial effectors
Nat. Rev. Microbiol.
2011
, vol. 
9
 
168
Smith
K.
Humphreys
D.
Hume
P. J.
Koronakis
V.
Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation
Cell Host Microbe
2010
, vol. 
7
 (pg. 
13
-
24
)
[PubMed]
169
Sarantis
H.
Balkin
D. M.
De Camilli
P.
Isberg
R. R.
Brumell
J. H.
Grinstein
S.
Yersinia entry into host cells requires Rab5-dependent dephosphorylation of PI(4,5)P2 and membrane scission
Cell Host Microbe
2012
, vol. 
11
 (pg. 
117
-
128
)
[PubMed]
170
Moorhead
A. M.
Jung
J.-Y.
Smirnov
A.
Kaufer
S.
Scidmore
M. A.
Multiple host proteins that function in phosphatidylinositol-4-phosphate metabolism are recruited to the chlamydial inclusion
Infect. Immun.
2010
, vol. 
78
 (pg. 
1990
-
2007
)
[PubMed]
171
Kühbacher
A.
Dambournet
D.
Echard
A.
Cossart
P.
Pizarro-Cerdá
J.
Phosphatidylinositol 5-phosphatase oculocerebrorenal syndrome of Lowe protein (OCRL) controls actin dynamics during early steps of Listeria monocytogenes infection
J. Biol. Chem.
2012
, vol. 
287
 (pg. 
13128
-
13136
)
[PubMed]
172
Weber
S. S.
Ragaz
C.
Hilbi
H.
The inositol polyphosphate 5-phosphatase OCRL1 restricts intracellular growth of Legionella, localizes to the replicative vacuole and binds to the bacterial effector LpnE
Cell. Microbiol.
2009
, vol. 
11
 (pg. 
442
-
460
)
[PubMed]
173
Niebuhr
K.
Giuriato
S.
Pedron
T.
Philpott
D. J.
Gaits
F.
Sable
J.
Sheetz
M. P.
Parsot
C.
Sansonetti
P. J.
Payrastre
B.
Conversion of PtdIns(4,5)P2 into PtdIns(5)P by the S. flexneri effector IpgD reorganizes host cell morphology
EMBO J.
2002
, vol. 
21
 (pg. 
5069
-
5078
)
[PubMed]
174
Ramel
D.
Lagarrigue
F.
Pons
V.
Mounier
J.
Dupuis-Coronas
S.
Chicanne
G.
Sansonetti
P. J.
Gaits-Iacovoni
F.
Tronchere
H.
Payrastre
B.
Shigella flexneri infection generates the lipid PI5P to alter endocytosis and prevent termination of EGFR signaling
Sci. Signal.
2011
, vol. 
4
 pg. 
ra61
 
[PubMed]
175
Norris
F. A.
Wilson
M. P.
Wallis
T. S.
Galyov
E. E.
Majerus
P. W.
SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase
Proc. Natl. Acad. Sci. U.S.A.
1998
, vol. 
95
 (pg. 
14057
-
14059
)
[PubMed]
176
Marcus
S. L.
Wenk
M. R.
Steele-Mortimer
O.
Finlay
B. B.
A synaptojanin-homologous region of Salmonella typhimurium SigD is essential for inositol phosphatase activity and Akt activation
FEBS Lett.
2001
, vol. 
494
 (pg. 
201
-
207
)
[PubMed]
177
Hernandez
L. D.
Hueffer
K.
Wenk
M. R.
Galán
J. E.
Salmonella modulates vesicular traffic by altering phosphoinositide metabolism
Science
2004
, vol. 
304
 (pg. 
1805
-
1807
)
[PubMed]
178
Vergne
I.
Chua
J.
Lee
H.-H.
Lucas
M.
Belisle
J.
Deretic
V.
Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
4033
-
4038
)
[PubMed]
179
Balla
T.
Szentpetery
Z.
Kim
Y. J.
Phosphoinositide signaling: new tools and insights
Physiology
2009
, vol. 
24
 (pg. 
231
-
244
)
[PubMed]
180
Idevall-Hagren
O.
Dickson
E. J.
Hille
B.
Toomre
D. K.
De Camilli
P.
Optogenetic control of phosphoinositide metabolism
Proc. Natl. Acad. Sci. U.S.A.
2012
, vol. 
109
 (pg. 
E2316
-
E2323
)
[PubMed]
181
Tronchère
H.
Laporte
J.
Pendaries
C.
Chaussade
C.
Liaubet
L.
Pirola
L.
Mandel
J.-L.
Payrastre
B.
Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells
J. Biol. Chem.
2004
, vol. 
279
 (pg. 
7304
-
7312
)
[PubMed]
182
Jean
S.
Cox
S.
Schmidt
E. J.
Robinson
F. L.
Kiger
A.
Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling
Mol. Biol. Cell
2012
, vol. 
23
 (pg. 
2723
-
2740
)
[PubMed]
183
Zou
J.
Marjanovic
J.
Kisseleva
M. V.
Wilson
M.
Majerus
P. W.
Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis
Proc. Natl. Acad. Sci.
2007
, vol. 
104
 (pg. 
16834
-
16839
)
184
Taguchi-Atarashi
N.
Hamasaki
M.
Matsunaga
K.
Omori
H.
Ktistakis
N. T.
Yoshimori
T.
Noda
T.
Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy
Traffic
2010
, vol. 
11
 (pg. 
468
-
478
)
[PubMed]
185
Sanchez-Juan
P.
Bishop
M. T.
Aulchenko
Y. S.
Brandel
J.-P.
Rivadeneira
F.
Struchalin
M.
Lambert
J.-C.
Amouyel
P.
Combarros
O.
Sainz
J.
, et al. 
Genome-wide study links MTMR7 gene to variant Creutzfeldt–Jakob risk
Neurobiol. Aging
2012
, vol. 
33
 pg. 
1487.e1421–1487.e1428
 
186
Berger
P.
Berger
I.
Schaffitzel
C.
Tersar
K.
Volkmer
B.
Suter
U.
Multi-level regulation of myotubularin-related protein-2 phosphatase activity by myotubularin-related protein-13/set-binding factor-2
Hum. Mol. Genet.
2006
, vol. 
15
 (pg. 
569
-
579
)
[PubMed]
187
Azzedine
H.
Bolino
A.
Taïeb
T.
Birouk
N.
Di Duca
M.
Bouhouche
A.
Benamou
S.
Mrabet
A.
Hammadouche
T.
Chkili
T.
, et al. 
Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot–Marie–Tooth disease associated with early-onset glaucoma
Am. J. Hum. Genet.
2003
, vol. 
72
 (pg. 
1141
-
1153
)
[PubMed]
188
Yang
G.
Zhou
X.
Zhu
J.
Liu
R.
Zhang
S.
Coquinco
A.
Chen
Y.
Wen
Y.
Kojic
L.
Jia
W.
Cynader
M. S.
JNK3 couples the neuronal stress response to inhibition of secretory trafficking
Sci. Signal.
2013
, vol. 
6
 pg. 
ra57
 
[PubMed]
189
Pirruccello
M.
Nandez
R.
Idevall-Hagren
O.
Alcazar-Roman
A.
Abriola
L.
Berwick
S.
Lucast
L.
Morel
D.
De Camilli
P.
Identification of inhibitors of inositol 5-phosphatases through multiple screening strategies
ACS Chem. Biol.
2014
 
doi:10.1021/cb500161z