Of the seven phosphoinositides, PtdIns5P remains the most enigmatic. However, recent research has begun to elucidate its physiological functions. It is now clear that PtdIns5P is found in several distinct subcellular locations, and the identification of a number of PtdIns5P-binding proteins points to its involvement in a variety of key processes, including signal transduction, membrane trafficking and regulation of gene expression. Although the mechanisms that control its turnover are not yet fully understood, the existence of multiple pathways for PtdIns5P regulation is consistent with this emerging versatility.

Introduction

The phosphoinositide phospholipids are well established as essential regulatory molecules in eukaryotic cells, and play key roles in many diverse cellular processes. The physiological functions of prominent members of the group, such as PtdIns(3,4,5)P3, the product of the critically important Class I PI3Ks (phosphoinositide 3-kinases), are understood in detail. In contrast, much less is known about other phosphoinositides. In particular, the monophosphorylated phosphoinositide PtdIns5P remains incompletely understood. However, evidence is accumulating that PtdIns5P has essential functions at several subcellular locations, and recent work has begun to unravel some of its mysteries.

Structure and localization

As with the other phosphoinositides, PtdIns5P is a phosphorylated derivative of PtdIns, consisting of an inositol phosphate headgroup attached via a phosphodiester linkage to diacylglycerol. The headgroup possesses a single phosphate group at position 5 of the inositol ring (Figure 1a). Consistent with a role in basic cellular processes, PtdIns5P is constitutively present in many cell types [1], at levels roughly 100-fold lower than those of the most abundant monophosphorylated phosphoinositide, PtdIns4P [1,2], and equivalent to those of the other monophosphorylated phosphoinositide PtdIns3P [2], although precise values vary [1,3]. Importantly, several physiological and pathological stimuli alter PtdIns5P levels, suggesting that, in addition to housekeeping functions, it also possesses signalling roles. Thrombin [4], insulin [1,5] and T-cell activation [6] stimulate 2-4-fold PtdIns5P increases in appropriate cell types, whereas histamine causes a 2-fold decrease [7]. PtdIns5P is also markedly elevated in cells infected with the pathogenic bacterium Shigella flexneri [8] or transformed with the oncogenic tyrosine kinase NPM-ALK (nucleophosmin anaplastic lymphoma kinase) [9], whereas pro-apoptotic stress elevates PtdIns5P within the nucleus [10].

PtdIns5P structure and turnover

Figure 1
PtdIns5P structure and turnover

(a) The headgroup of PtdIns5P possesses a single phosphate at position 5, and is linked to diacylglycerol (shown with the 1-stearoyl-2-arachidonoyl fatty acid composition thought to predominate in phosphoinositides) through a phosphodiester linkage. Phosphates are shown as a circled P. (b) PtdIns5P (centre) can be produced and removed by a number of routes. Phosphorylation of PtdIns by PIKfyve or PIP5K occurs in vitro, whereas PTPMT1 dephosphorylates PtdIns5P. Dephosphorylation of either PtdIns(4,5)P2 [by phosphatidylinositol 4,5-bisphosphate 4-phosphatases (PIP 4-Pase)], or PtdIns(3,5)P2 [by myotubularin family phosphatases (MTMs)] also produces PtdIns5P. PI3K converts PtdIns5P into PtdIns(3,5)P2in vitro, but this pathway is unlikely to operate in vivo, and the major physiological route of PtdIns(3,5)P2 production involves phosphorylation of the phosphoinositide PtdIns3P by PIKfyve (not shown). The main route of PtdIns5P removal involves its phosphorylation to PtdIns(4,5)P2 by PIP4K. Thicker arrows indicate pathways known to operate in vivo.

Figure 1
PtdIns5P structure and turnover

(a) The headgroup of PtdIns5P possesses a single phosphate at position 5, and is linked to diacylglycerol (shown with the 1-stearoyl-2-arachidonoyl fatty acid composition thought to predominate in phosphoinositides) through a phosphodiester linkage. Phosphates are shown as a circled P. (b) PtdIns5P (centre) can be produced and removed by a number of routes. Phosphorylation of PtdIns by PIKfyve or PIP5K occurs in vitro, whereas PTPMT1 dephosphorylates PtdIns5P. Dephosphorylation of either PtdIns(4,5)P2 [by phosphatidylinositol 4,5-bisphosphate 4-phosphatases (PIP 4-Pase)], or PtdIns(3,5)P2 [by myotubularin family phosphatases (MTMs)] also produces PtdIns5P. PI3K converts PtdIns5P into PtdIns(3,5)P2in vitro, but this pathway is unlikely to operate in vivo, and the major physiological route of PtdIns(3,5)P2 production involves phosphorylation of the phosphoinositide PtdIns3P by PIKfyve (not shown). The main route of PtdIns5P removal involves its phosphorylation to PtdIns(4,5)P2 by PIP4K. Thicker arrows indicate pathways known to operate in vivo.

Distinct phosphoinositides are typically enriched in particular subcellular compartments, and PtdIns5P also displays this characteristic, although its subcellular location has not been rigorously defined. A nuclear PtdIns5P pool, which fluctuates during progression through the cell cycle and in response to stress, has been extensively characterized [10,11]. However, most PtdIns5P is located outside the nucleus [1,12]. Cell fractionation has revealed that, under resting conditions, most of this PtdIns5P is in the plasma membrane, with the remainder being largely in a fraction enriched in Golgi and SER (sarco/endoplasmic reticulum) markers [1]. The location of the PtdIns5P pool(s) that is regulated by agonists remains to be determined.

PtdIns5P regulation

Several distinct pathways have the potential to generate PtdIns5P, but their relative contributions to its regulation in vivo are uncertain (Figure 1b). The other monophosphorylated phosphoinositides are produced by phosphorylation of PtdIns, but a purely PtdIns-specific 5-kinase has not been identified. Instead, somewhat unusually for a phosphoinositide, phosphatases play an important role in regulating PtdIns5P production.

Two related lipid kinases, the PIP5Ks (phosphatidylinositol 4-phosphate 5-kinases) [the main function of which is to generate the phosphoinositide PtdIns(4,5)P2] and PIKfyve [the main function of which is to produce the phosphoinositide PtdIns(3,5)P2] both phosphorylate PtdIns to PtdIns5P in vitro [13,14], but whether they do so in vivo is uncertain. PtdIns5P production by the PIP5Ks has not been explored, whereas PIKfyve is strongly implicated in PtdIns5P regulation: PIKfyve overexpression increases cellular PtdIns5P [3], whereas mice lacking one copy of the gene encoding it have reduced PtdIns5P levels [15]. PtdIns5P is also reduced in mice lacking Vac14, a PIKfyve regulatory protein [16], and following siRNA (small interfering RNA) knockdown of PIKfyve in NPM-ALK-transformed cells [9]. However, interpretation of these data is not straightforward, as PtdIns5P can also be produced from the major product of PIKfyve, PtdIns(3,5)P2, by phosphatases of the myotubularin family [17]. Cellular PtdIns(3,5)P2 levels are considerably lower than those of PtdIns5P [18], but overexpression of myotubularin-1 enhances PtdIns5P production in osmotically stressed muscle cells [19], and myotubularin activity is required for dehydration-induced PtdIns5P production in Arabidopsis [20], suggesting that PtdIns(3,5)P2 dephosphorylation plays a major role in generating PtdIns5P, at least in responses to osmotic stress.

PtdIns5P can also be produced by dephosphorylation of PtdIns(4,5)P2. This pathway was first identified in a pathological context, with the discovery that the S. flexneri virulence factor IpgD is a PtdIns(4,5)P2 4-phosphatase [8], responsible for the profound increases in PtdIns5P in S. flexneri-infected cells. Subsequently, two human genes encoding proteins with this activity, now termed PtdIns(4,5)P2 4-phosphatases I and II, were identified [12,21]. Overexpression of the type I isoform significantly increases basal PtdIns5P [12], but its knockdown using siRNA does not affect basal PtdIns5P, or the PtdIns5P increase provoked in HeLa cells by the phosphotyrosine phosphatase inhibitor pervanadate [22]. In resting cells, PtdIns(4,5)P2 4-phosphatases localize to late endosomes/lysosomes [21], but the type I isoform translocates to the nucleus after pro-apoptotic stress [12], possibly regulating stress-induced nuclear PtdIns5P production [10].

Most phosphoinositides are broken down by dephosphorylation, but PtdIns5P is again unusual in that its major route of catabolism involves its phosphorylation. A PtdIns5P-specific phosphatase {initially termed PLIP (phosphatase and tensin homologue deleted on chromosome 10-like phosphatase) [23,24], and renamed PTPMT1 (protein tyrosine phosphatase localized to mitochondrion 1) [25]} has been identified. However, it is restricted to mitochondria [24], which contain negligible PtdIns5P [25], and its physiological significance for PtdIns5P regulation is unclear. As the ability of other phosphatases to dephosphorylate PtdIns5P has not been established, the contribution of dephosphorylation to PtdIns5P removal remains uncertain. However, the phosphorylation of PtdIns5P to PtdIns(4,5)P2 unquestionably plays a major role in PtdIns5P regulation.

PtdIns5P phosphorylation is catalysed by the PIP4Ks (phosphatidylinositol 5-phosphate 4-kinases), of which three mammalian isoforms (α, β and γ) are known. PIP4Kα is the most potent, exhibiting 2000-fold greater activity than PIP4Kβ [26,27]. PIP4Kγ lacks catalytic activity [28]; however, its shRNA (small hairpin RNA)-mediated knockdown results in PtdIns5P elevation in SER/Golgi-enriched cell fractions [1], suggesting a role in PtdIns5P regulation at this location. This finding may be attributable to PIP4Kγ heterodimerization with PIP4Kα [2628]. Indeed, the primary role of PIP4Kγ, and of PIP4Kβ, which also oligomerizes with PIP4Kα, may actually be to target PIP4Kα to specific subcellular locations [2628]. Certainly, the targeting of PIP4Kα to the nucleus largely requires its interaction with PIP4Kβ [26,27], which is predominantly nuclear [29,30]. The effect of PIP4Kγ knockdown on endomembrane PtdIns5P content is consistent with the known subcellular distribution of this isoform [28,31], and may result from PIP4Kα mislocalization.

Although PtdIns5P can be phosphorylated to PtdIns(3,5)P2in vitro by Class I PI3K [2], whether this reaction occurs in vivo is not known. However, the fact that PtdIns5P levels exceed those of PtdIns(3,5)P2 [18], whereas PtdIns(4,5)P2 is significantly more abundant, is consistent with the idea that the PIP4K-mediated pathway is of most importance in regulating PtdIns5P.

As expected for enzymes predominantly responsible for removing a potential signalling mediator, PIP4Kα and PIP4β are constitutively active. Nuclear PtdIns5P levels are boosted following oxidative stress by PIP4Kβ inhibition [10], achieved through its phosphorylation by p38 MAPK (mitogen-activated protein kinase). Although the impact of oxidative stress on PIP4Kα has not been reported, conservation of the inhibitory phosphorylation site suggests that it may be similarly regulated. Protein kinase D phosphorylation at distinct sites also inhibits PIP4Kα [32]. These findings suggest that transient inhibition of PIP4Ks contributes to the PtdIns5P increases seen in response to stimuli. Alterations in PIP4K subcellular localization may also regulate their access to PtdIns5P: PIP4Ks translocate to the membrane and cytoskeleton of activated platelets [33,34], and PIP4Kα associates with the plasma membrane of light-activated retinal rod cells [35].

Function

Phosphoinositides exert their physiological effects through their interaction with specific binding proteins. Identification of the binding partners of PtdIns5P has been relatively slow, but several examples are now known. An important breakthrough came with the discovery that the nuclear protein ING2, which regulates p53 acetylation, binds to PtdIns5P via its PHD (plant homeodomain) domain [36]. Other PHD-domain containing proteins, including ING1, ACF (ATP-dependent chromatin-remodelling factor) [36] and the Arabidopsis gene regulatory protein ATX1 [37] also interact with PtdIns5P. Importantly, manipulation of nuclear PtdIns5P modifies ING2 localization and function [10,36]. Nuclear PtdIns5P is also implicated in activating the ubiquitin ligase Cul3-SPOP [38], via an incompletely understood mechanism involving p38 MAPK activation. These studies indicate that nuclear PtdIns5P plays important roles in regulating nuclear protein function. However, PtdIns5P generation outside the nucleus may also influence gene expression. Overexpression of an Arabidopsis myotubularin causes relocation of ATX1 to the cytoplasm through PtdIns5P elevation [20], and similar sequestration of ATX1 away from its nuclear targets by elevated PtdIns5P is likely to underlie the down-regulation of certain ATX1-regulated genes in response to dehydration. Whether similar mechanisms operate in animal cells remains to be established, but the concept adds a further dimension to PtdIns5P function.

The first non-nuclear proteins to be identified as transducers of PtdIns5P signals are members of the Dok family [6]. Dok proteins possess tandem PTB (phosphotyrosine-binding) and PH (pleckstrin homology) domains, and the PH domains of Dok-1, Dok-2 [6], Dok-4 and Dok-5 [39] all bind PtdIns5P. Manipulation of PtdIns5P levels regulates Dok-1 and Dok-2 phosphorylation following T-cell activation, the PH domains being required for this modification [6].

The PH domain of Dok-5, which exhibits high selectivity for PtdIns5P, has been used as a tool to sequester endogenous PtdIns5P [39]. Interestingly, its overexpression reduces T-cell receptor-stimulated activation of Src family tyrosine kinases, and of the serine/threonine kinase Akt, an important effector of PI3K, implicating PtdIns5P in the regulation of these processes. Significantly, PtdIns5P elevation provoked by S. flexneri infection or IpgD overexpression also activates Akt via tyrosine kinase-dependent PI3K activation [40,41]. Furthermore, PtdIns5P has been implicated in prolonging or enhancing PI3K/Akt signalling in responses to both insulin and EGF (epidermal growth factor). Insulin-stimulated increases in PtdIns(3,4,5)P3 levels are reduced by approximately 25% when PIP4Kβ is overexpressed, whereas levels of its metabolite PtdIns(3,4)P2 are markedly increased [42]. Moreover, the rate at which both PtdIns(3,4,5)P3 and Akt are inactivated by dephosphorylation is enhanced by PIP4K. Assuming that PIP4Kβ overexpression decreases PtdIns5P, which has not formally been shown, these results implicate PtdIns5P in promoting PI3K/Akt signalling, possibly by attenuating PtdIns(3,4,5)P3 dephosphorylation. However, in HeLa cells expressing IpgD, PtdIns(3,4,5)P3 dephosphorylation is unaffected [41]. Instead, prolonged Akt signalling in this system results from impaired Akt dephosphorylation, achieved through the inhibition of PP2A (protein phosphatase 2A), which becomes tyrosine-phosphorylated when PtdIns5P levels are high.

PtdIns5P may also possess functions outside the nucleus that are independent of PI3K. Microinjection of PtdIns5P provokes cytoskeletal rearrangement in a PI3K-independent fashion [5], and this process has been suggested to play a role in insulin-dependent glucose uptake in 3T3-L1 adipocytes. Interestingly, microinjection of a construct composed of tandem repeats of the PtdIns5P-binding ING2 PHD domain interferes with the insertion of the insulin-regulated GLUT4 (glucose transporter 4) into the plasma membrane of these cells [5]. An important role for PtdIns5P in responses to insulin is suggested further by the insulin-hypersensitivity of PIP4Kβ-knockout mice [43], although, given the nuclear location of PIP4Kβ, it is possible that this phenotype arises from alterations in gene expression rather than from compromised PtdIns5P removal outside the nucleus. Moreover, since PI3K/Akt signalling, an apparent target of PtdIns5P, is also essential for insulin-stimulated glucose uptake, further work is needed to clarify the exact role of PtdIns5P in insulin signalling.

In addition to biochemical studies, a phylogenetic analysis of PtdIns5P regulatory proteins has led to the hypothesis that PtdIns5P is involved in membrane trafficking between late endosomes and the plasma membrane [44]. Cell fractionation suggests that PtdIns5P is enriched in SER/Golgi membranes rather than endosomes [1], but this finding is still consistent with a membrane trafficking role. Interestingly, PtdIns5P stimulates the activity of myotubularins [17], which also possess important membrane trafficking functions. As these proteins also generate PtdIns5P (see above), this possibly indicates the existence of a positive-feedback loop in PtdIns5P production. Although further verification of the putative membrane trafficking role of PtdIns5P is required, it is possible to speculate that such a function is more likely to involve the PtdIns5P pool present in unstimulated cells, with PtdIns5P generated upon stimulation fulfilling other purposes.

Although recent attention has focused on the role of PtdIns5P as a signalling mediator, it is essential not to overlook the fact that the product of the PIP4Ks, PtdIns(4,5)P2, is itself an essential regulatory molecule. PtdIns(4,5)P2 generated by PIP4Ks is involved in microparticle shedding in platelets [34,45], and PtdIns(4,5)P2 production from nuclear PtdIns5P is required for responses to vitamin D3 [46]. In addition to its roles in regulating protein function, PtdIns5P regulation may thus also influence specific functions of PtdIns(4,5)P2.

In summary, although PtdIns5P has been slow to give up its secrets, it is now clear that it plays multiple roles in cellular function. Much remains to be discovered. First, although PtdIns5P has emerged as a possible activator of protein kinases, the mechanisms by which it stimulates tyrosine kinase and p38 MAPK signalling remain to be identified. Secondly, the contribution of the various pathways of PtdIns5P production to its turnover requires clarification, although, given the probable existence of multiple functionally distinct PtdIns5P pools, it is possible that more than one of these pathways will turn out to be physiologically important. Finally, clearer identification of the membranes enriched in PtdIns5P, and of the subcellular location of the changes provoked by stimulation, is also required. Nevertheless, despite these ongoing uncertainties, recent research shows that PtdIns5P can now take its rightful place with the other phosphoinositides as a powerful mediator of cellular signalling.

Note added in proof (received 29 November 2011)

Since the present article was submitted, the physiological function of PTPMT1 has been shown to be dephosphorylation of phosphatidylgly cerophosphate, not PtdIns 5P [47]. It has also been shown that IpgD-dependent Akt activation occurs due to transactivation of the EGF receptor [48].

Signalling 2011: a Biochemical Society Centenary Celebration: A Biochemical Society Focused Meeting held at the University of Edinburgh, U.K., 8–10 June 2011. Organized and Edited by Nicholas Brindle (Leicester, U.K.), Simon Cook (The Babraham Institute, U.K.), Jeff McIlhinney (Oxford, U.K.), Simon Morley (University of Sussex, U.K.), Sandip Patel (University College London, U.K.), Susan Pyne (University of Strathclyde, U.K.), Colin Taylor (Cambridge, U.K.), Alan Wallace (AstraZeneca, U.K.) and Stephen Yarwood (Glasgow, U.K.).

Abbreviations

     
  • EGF

    epidermal growth factor

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • NPM-ALK

    nucleophosmin anaplastic lymphoma kinase

  •  
  • PH

    pleckstrin homology

  •  
  • PHD

    plant homeodomain

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PIP4K

    phosphatidylinositol 5-phosphate 4-kinase

  •  
  • PIP5K

    phosphatidylinositol 4-phosphate 5-kinase

  •  
  • PTPMT1

    protein tyrosine phosphatase localized to mitochondrion 1

  •  
  • SER

    sarco/endoplasmic reticulum

  •  
  • siRNA

    small interfering RNA

Funding

We thank the Biotechnology and Biological Sciences Research Council (Doctoral Training Accounts studentship to D.L.G.), the Royal Society [grant number R00461], the AG Laventis Foundation (scholarship to C.T.) and Diabetes UK (Ph.D. studentship to A.J.R.).

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