Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.

Introduction

Cell surface receptors are key players modulating critical cellular processes such as survival, proliferation, migration and invasion. Therefore, up-regulation of cell surface receptors, such as growth factor receptors and integrin cell-adhesion molecules, leads to constitutive activation of downstream signalling pathways. Persistence of these pro-proliferative, pro-survival, pro-migratory and pro-invasive signals is well recognized as hallmarks of cancer and drives multiple steps of the tumorigenic development [1]. Indeed, up-regulation of many cell surface receptors is linked with cancer predisposition and poor prognosis. Following their initial activation by cognate ligand, cell surface receptors are ubiquitinated, internalized and sorted for degradation or recycled to the cell surface [2,3]. The factors responsible for endosomal sorting and degradation of these receptors are therefore crucial to dampening chronic downstream signalling and preventing cancer predisposition. The co-ordination of ubiquitinated cell surface receptors internalization and delivery to the lysosomal degradation pathway is orchestrated by the components of the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery (for a review, see refs [35]).

ESCRT characteristics and physiological functions

The main function of the ESCRT complexes is to remodel early endosome membranes in order to sort ubiquitinated receptors (originally at the cell surface) into multi-vesicular bodies (MVBs), which are destined to degradation by the lysosomes [6]. The ESCRTs form an evolutionarily conserved machinery composed of five distinct complexes (ESCRT-0, -I, -II, -III and the Vps4 complex), each constituted of two or more subunits involved in membrane bending and scission [710]. Every ESCRT complex has a clear and co-ordinate division of tasks and works concomitantly on membrane deformation and abscission in order to sort ubiquitinated membrane receptors in the endosomes [11]. In this mini-review, the human nomenclature is employed to designate ESCRT subunits (see Table 1). The ESCRT-0 complex is composed of the Hrs and the STAM1/2 proteins [7]. This complex is a cargo-recognition module responsible for the ubiquitinated-activated receptors clustering in endosomal membranes, which initiate MVB formation through the capacity of the ESCRT-0 components to bind endosome-enriched phospholipids [4,12]. Classically, the ESCRT-I complex is a heteromeric rod-shaped complex consisting of TSG101, hVps28, Vps37 and hMvb12 [10,13]. However, an alternative ESCRT-I complex composed of TSG101, hVps28, Vps37 and UBAP1 has been previously described [14,15]. Additionally, two BRO1-like domains containing ESCRT proteins, Alix and Histidine-Domain Protein Tyrosine Phosphatase (HD-PTP), involved in the recognition of specific cargo, have been identified in ESCRT-I complexes [1517]. Through their capability to bind ubiquitin and interact with multiple proteins, the ESCRT-I components consolidate and stabilize the concentration of the ubiquitinated cell surface receptors in the endosomal membrane and form a bridge between ESCRT-0 and ESCRT-II complexes [1820]. The ESCRT-II complex is a Y-shaped heterotetramer complex consisting of one subunit of EAP30, EAP45 and two subunits of EAP20, which binds simultaneously to ubiquitinated cargo, membrane phospholipids, ESCRT-I and ESCRT-III complexes [2124]. Both ESCRT-I and ESCRT-II complexes initiate the budding of the endosomal membrane to eventually generate intraluminal vesicles [4]. The ESCRT-III complex consists of four core subunits (CHMP6, CHMP4, CHMP3 and CHMP2) and three accessory proteins (CHMP1A, CHMP1B and CHMP5) that are transiently recruited to ubiquitinated receptor-rich endosomal membranes to mediate their de-ubiquitination (and thus recycling of the ubiquitin moieties) and finalize their incorporation into MVBs by orchestrating membrane budding and scission [4,25]. Finally, the class I AAA-ATPase SDK1 of the Vps4 complex catalyses the dissociation of the membrane-bound ESCRT-III complex, a step that also requires its multimerization with the LIP5 protein [25].

Table 1
List of Classical ESCRT components (human nomenclature)
Complexes Subunit Complete subunit name 
ESCRT-0 Hrs Hepatocyte growth factor-regulated tyrosine kinase substrate 
STAM ½ Signal transducing adaptor molecule 1/2 
ESCRT-I Tsg101 Tumour susceptibility gene 101 
hVps28 Human vacuolar protein sorting 28 
Vps37A, B, C Vacuolar protein sorting 37A, B, C 
hMvb12A, B Human MVB 12A, B 
ESCRT-II EAP45 ELL-associated protein of 45 kDa 
EAP30 ELL-associated protein of 30 kDa 
EAP20 ELL-associated protein of 20 kDa 
ESCRT-III CHMP6 Charged MVB proteins 6 
CHMP4A, B, C Charged MVB proteins 4A, B, C 
CHMP3 Charged MVB proteins 3 
CHMP2A, B Charged MVB proteins 2A, B 
Vps4 SKD1 Suppressor of K+ transport defect 1 
CHMP5 Charged MVB proteins 5 
LIP5 LYST-interacting protein 5 
Complexes Subunit Complete subunit name 
ESCRT-0 Hrs Hepatocyte growth factor-regulated tyrosine kinase substrate 
STAM ½ Signal transducing adaptor molecule 1/2 
ESCRT-I Tsg101 Tumour susceptibility gene 101 
hVps28 Human vacuolar protein sorting 28 
Vps37A, B, C Vacuolar protein sorting 37A, B, C 
hMvb12A, B Human MVB 12A, B 
ESCRT-II EAP45 ELL-associated protein of 45 kDa 
EAP30 ELL-associated protein of 30 kDa 
EAP20 ELL-associated protein of 20 kDa 
ESCRT-III CHMP6 Charged MVB proteins 6 
CHMP4A, B, C Charged MVB proteins 4A, B, C 
CHMP3 Charged MVB proteins 3 
CHMP2A, B Charged MVB proteins 2A, B 
Vps4 SKD1 Suppressor of K+ transport defect 1 
CHMP5 Charged MVB proteins 5 
LIP5 LYST-interacting protein 5 

From their action on the formation of MVBs leading to delivery of ubiquitinated receptors to the lysosome for degradation, ESCRT components regulate the presence of cell surface receptors at the plasma membrane and the downstream signalling events driven by these receptors. For instance, it was extensively reported that ESCRTs are required for EGFR degradation. Consequently, the knockdown of Hrs, TSG101, EAP30 and CHMP3 impairs EGFR degradation [18]. Indeed, constitutive EGFR activation and downstream MAPK signalling were observed upon Hrs, TSG101 and Vsp37 down-regulation [12,26]. Accordingly, ESCRT-I and -III depletion significantly delayed EGFR recycling [27]. In addition to EGFR, the ESCRT machinery is indispensable for the degradation of activated integrin α5β1 and prevents its endosomal accumulation [28]. Consistently, we recently reported that UBAP1 and HD-PTP are crucial for lysosomal degradation of integrin α5β1 cargo [29]. Their depletion favoured recycling of integrin α5β1 back to the plasma membrane, resulting in amplification of downstream signalling, and potentiated migration and invasion [29]. BST-2016-0332CTB2 

Table 2
Expression status of ESCRT subunits in different types of human cancer
Complexes Subunit Expression Cancer type 
ESCRT-0 Hrs Up-regulated Stomach, colon, liver, cervix and melanoma (51) 
ESCRT-I Tsg101 Up-regulated Breast (52), papillary thyroid (53) and colorectal carcinomas (54) 
Vps37A Down-regulated Hepatocellular carcinoma (56) 
UBAP1 Down-regulated Nasopharyngeal carcinoma (57) 
ESCRT-III CHMP4C Up-regulated Ovarian carcinoma (55) 
Vps4 SKD1 Down-regulated Breast cancer (59) 
Up-regulated Non-small-cell lung cancer (61) 
Complexes Subunit Expression Cancer type 
ESCRT-0 Hrs Up-regulated Stomach, colon, liver, cervix and melanoma (51) 
ESCRT-I Tsg101 Up-regulated Breast (52), papillary thyroid (53) and colorectal carcinomas (54) 
Vps37A Down-regulated Hepatocellular carcinoma (56) 
UBAP1 Down-regulated Nasopharyngeal carcinoma (57) 
ESCRT-III CHMP4C Up-regulated Ovarian carcinoma (55) 
Vps4 SKD1 Down-regulated Breast cancer (59) 
Up-regulated Non-small-cell lung cancer (61) 

In addition to MVB biogenesis, ESCRTs are involved in several essential cellular processes such as cytokinesis, viral budding, as well as exosome secretion and autophagy [3033]. Indeed, it was proposed that the ESCRT-I components TSG101 and Alix, both localized to the constricted midbodies during the final stage of cytokinesis, are playing a critical role in cell abscission by recruiting ESCRT-III components [34]. Interestingly, while viral budding of HIV-1 does not require ESCRT-0, ESCRT-II and CHMP6, it is mediated by the interaction of TSG101 with the ubiquitinated viral Gag protein [23]. In addition, Alix has been implicated in exosome-mediated protein sorting independently of cargo ubiquitination, suggesting an ESCRT-independent function [35,36]. ESCRTs could also be responsible for the fusion of autophagosomes with the endolysosomal system, since autophagosomes accumulated upon ESCRT depletion [37]. The function of ESCRT-I and ESCRT-III complexes in the neurite scission event during pruning, a neuronal remodelling process, has also been reported [38]. Moreover, ESCRT proteins are recruited within seconds to plasma membrane wounds, thus playing a critical role in plasma membrane repair mechanism [39]. Finally, the ESCRT-III complex appears responsible for nuclear envelope re-formation during the telophase stage of mitosis [40]. The few examples above illustrate the wide range of ESCRT functions.

Role of ESCRTs in diseases

Consistent with its essential function in many cell signalling pathways, dysfunctional ESCRT machinery due to gene mutations has been linked to several diseases [41]. For instance, defects in the endosomal–lysosomal system are a major cause of several neurodegenerative diseases [41]. More specifically, endosomal abnormalities in neuronal cells have been associated with Alzheimer's disease and amyotrophic lateral sclerosis [42,43]. In addition, the fact that Huntington's and Parkinson's diseases are characterized by the accumulation of intracellular ubiquitinated protein aggregates might be associated with MVB accumulation caused by the loss of ESCRT function [41]. ESCRT and MVB formation are the key players of lysosomal degradation of ion channels and are crucial for ion homeostasis in different tissues [41]. Therefore, chronic diseases caused by abnormalities in the levels of ion channels, such as the renal pseudohypoaldosteronism type I and hypertension leading to cardiovascular disease, have been associated with defective ESCRT-mediated endocytic function [41,4446]. Finally, several classes of enveloped viruses utilize the ESCRT machinery for budding out of host cells via an interaction between TSG101 and Gag proteins of HIV, Ebola and HTLV [47,48].

ESCRT functions in cancer

Owing to their critical function in degradation of cell surface receptors, several reports have proposed a tumour suppressive gene (TSG) function of the ESCRT members [2,49]. However, both oncogenic and tumour suppressor functions of ESCRT components were suggested in various types of human cancer. As examples, Hrs is up-regulated in stomach, colon, liver, cervix and melanoma tumours [50]; TSG101 is up-regulated in breast cancer [51], papillary thyroid [52] and colorectal carcinomas [53]; and CHMP4C is up-regulated in ovarian carcinoma tissues [54]. In contrast, Vps37A is reduced in hepatocellular carcinoma (HCC) [55] and was reported as a growth inhibitory protein capable of decreasing the invasive potential of HCC cells [55]. Moreover, reduced expression levels of UBAP1 in nasopharyngeal carcinomas [56] and CHMP1A in pancreatic ductal adenocarcinomas [57] were reported. Furthermore, Vps4B is reduced in high-grade breast tumours (Stage IV) [58] and correlates negatively with EGFR levels [59]. Vps4B is overexpressed in non-small-cell lung cancer (NSCLC) and promotes cell proliferation and NSCLC progression [60]. While correlative expression levels and in vitro functional experiments suggested both positive and negative roles in cancer, the bona fide function of the ESCRT components in tumorigenesis had not been systematically demonstrated, since homozygous gene deletion of ESCRT components is embryonic lethal in mice and most ESCRT members are involved in other essential functions described above [5]. Strikingly, HD-PTP was recently identified as the first ESCRT component with tumour suppressive function in mammals in vivo.

HD-PTP structure and domains

Human HD-PTP is a 1636 amino acid protein of 185 kDa composed of five main domains (Figure 1) [61]. The BRO1-like domain is homologous to the yeast BRO1 and the mammalian Alix and Brox proteins and plays a role in endosomal sorting, ESCRT function and MVB biogenesis [62,63]. The V-domain is homologous to the ‘V-shaped’ domain of Alix, a flexible structure that acts as a hinge region allowing Alix open and closed conformations [64,65]. The V-domain of HD-PTP is responsible for the interaction with Lys63-linked polyubiquitinated substrates and for the mediation of HD-PTP interaction with the ESCRT-I component UBAP1 [14,66]. HD-PTP harbours a central proline-rich region initially named HIS (histidine-rich domain) that might recruit SH3-containing proteins. HD-PTP also possesses a classical tyrosine phosphatase domain comprising all the 10 protein tyrosine phosphatase (PTP) motifs defining this enzyme family [61,67,68]. Finally, HD-PTP has a proteolytic degradation-targeting motif, also known as a PEST sequence, which might regulate HD-PTP degradation and/or subcellular localization [69,70]. However, despite recent findings, the precise role of HD-PTP domains remains to be elucidated. HD-PTP was recently identified as an alternative ESCRT-I member, largely restricted to the early endosome [71,72], where it acts in close co-operation with ESCRT-0 components [73] and UBAP1 (ESCRT-I) to down-regulate multiple ubiquitinated cargos [29,74].

Schematic representation of the human HD-PTP protein.

Figure 1.
Schematic representation of the human HD-PTP protein.

Numbers correspond to amino acids of the human protein. HD-PTP domains are represented; BRO: Bro homology domain; V: V-shaped homology domain; PRR (HIS): proline-rich region initially named HIS (histidine-rich domain); PTP-like: protein tyrosine phosphatase-like domain; Pr: proteolytic degradation-targeting motif also known as the PEST motif. Divergence in the PTP motif 1 (Y1217 and H1223), 8 (E1357) and 9 (S1394) are indicated as well as the catalytic cysteine (C1392) required for PTP activity. The regions mediating the interaction with STAM (for which T145 is critical), UBAP1 (for which F678 is critical) and K63 ubiquitin chains are underlined.

Figure 1.
Schematic representation of the human HD-PTP protein.

Numbers correspond to amino acids of the human protein. HD-PTP domains are represented; BRO: Bro homology domain; V: V-shaped homology domain; PRR (HIS): proline-rich region initially named HIS (histidine-rich domain); PTP-like: protein tyrosine phosphatase-like domain; Pr: proteolytic degradation-targeting motif also known as the PEST motif. Divergence in the PTP motif 1 (Y1217 and H1223), 8 (E1357) and 9 (S1394) are indicated as well as the catalytic cysteine (C1392) required for PTP activity. The regions mediating the interaction with STAM (for which T145 is critical), UBAP1 (for which F678 is critical) and K63 ubiquitin chains are underlined.

HD-PTP is a pseudophosphatase

Based on its amino acid sequence, HD-PTP has been initially described as a classical non-transmembrane PTP. However, our group reported a rigorous enzymatic analysis demonstrating that HD-PTP does not harbour tyrosine or lipid phosphatase activity using the highly sensitive DiFMUP substrate and a panel of different phosphatidylinositol phosphates [75]. HD-PTP is also inert against a panel of 38 phosphopeptides [76]. In agreement with a catalytic inactive status, the HD-PTP primary sequence displays multiple divergences from the PTP consensus motifs that are structurally and catalytically incompatible with a proper PTP activity [68,76]. For instance, in the PTP motif 1, known as a phosphotyrosine recognition loop that restricts the substrate specificity to tyrosine-phosphorylated peptide, HD-PTP displays divergences similar to those observed in the two inactive receptor-like PTPs IA2 and IA2β. Another important alteration is located in PTP motif 8, where the aspartic acid (D) is replaced by a glutamic acid (E) in HD-PTP. This residue is known as the general acid catalyst and its replacement by an alanine residue considerably reduced PTP activity in PTP1B [77]. This alteration is also present in many inactive D2 domains of receptor PTPs. However, back mutation of this residue (E/D) was not sufficient to restore HD-PTP catalytically active [75]. Importantly, the lack of HD-PTP tyrosine phosphatase activity is largely caused by an evolutionarily conserved amino acid divergence of a key residue located in its PTP motif 9, since its back mutation (S1394A mutant) is sufficient to restore HD-PTP tyrosine phosphatase activity [75]. These results suggested that, as described for other inactive PTPs, the HD-PTP inactive PTP domain might act as a phosphotyrosine-binding module (also called STYX domain) and might control cell signalling pathways by preventing the dephosphorylation of its binding partners or by regulating their cellular localization [78,79]. Interestingly, a previous study reported a role for Mop (Drosophila homologue of mammalian HD-PTP) in border cell dissociation during Drosophila oogenesis [80]. In agreement with a pseudophosphatase function, the integrity and presence of the Mop PTP domain is not required for this activity. In contrast with our data, Lin et al. [81] showed that HD-PTP is an active phosphatase directly responsible for Src kinase dephosphorylation and inactivation. While several groups, including ours, had observed the effect of HD-PTP depletion on Src phosphorylation, the direct dephosphorylation of Src by HD-PTP phosphatase activity has not been corroborated yet. In fact, this activity might be independent of the HD-PTP catalytic function since it was not validated using a PTP chemical inhibitor (sodium orthovanadate) and/or an inactivating mutation of the PTP catalytic site (C/S) that are commonly used to confirm PTP specificity and exclude the presence of co-purified contaminated phosphatases [82]. Interestingly, a recent study supporting a pseudophosphatase function for the phosphatases of regenerating liver (PRLs) family might shed light on HD-PTP catalytic mechanism [83]. Indeed, PRLs possess an extremely slow hydrolysis rate and are rapidly inactivated by oxidation, limiting the production and the detection of dephosphorylated substrate and suggesting a non-canonical PTP function. While different substrates were used in the studies described above, the HD-PTP hydrolysis rate published by Zhang et al. [83] (245 nmol/min) is way slower than the reactivated HD-PTP hydrolysis rate observed upon S1394A mutation (184 pmol/min), suggesting that a mechanism similar to that seen with the PRLs might explain the conflicting reports on HD-PTP. However, further studies will be required to investigate this possibility.

HD-PTP tumour suppressor potential

The tumour suppressor function of HD-PTP was originally proposed based on its chromosomal localization [61]. Indeed, HD-PTP is encoded by the PTPN23 gene, located on the human 3p21.3 chromosomal region described as a tumour suppressor cluster frequently deleted in kidney, lung, breast and cervical tumours [8488]. Interestingly, the 3p21.3 tumour suppressor cluster is frequently hemizygously deleted in a variety of human tumours but rarely mutated on the remaining allele, suggesting a non-conventional haplo-insufficient TSG function [84,89,90]. In agreement, several studies suggested a putative HD-PTP tumour suppressor function. For instance, it was reported that overexpression of rat HD-PTP inhibits ras-mediated NIH3T3 transformation [91]. In addition, overexpression of HD-PTP in NEC8, a human testicular germ cell tumour cell line, suppressed soft agar colony formation in vitro and tumour formation in nude mice in vivo [92]. Furthermore, HD-PTP expression leads to colony growth reduction in human kidney cancer cell lines, independently of its phosphatase activity status. Indeed, HD-PTP inactive wild-type or the reactivated mutant (S1394A) had similar growth inhibitory effects, while expression of a truncated mutant, containing the Bro1 domain devoid of the central PRR and PTP domains, did not reduce colony formation, suggesting the functional importance of these domains [75]. Whereas these studies suggested a HD-PTP tumour suppressor potential, it was not confirmed in vivo by loss-of-function studies in animals.

Hemizygous deletion of HD-PTP predisposes to cancer

To study the HD-PTP tumour suppressor potential in vivo, our group generated a knockout mouse model [93]. The homozygous Ptpn23 deletion resulted in an embryonic lethal phenotype, suggesting an essential requirement during the embryonic development. Interestingly, we observed that the hemizygous Ptpn23 deletion predisposed mice to spontaneous lung adenoma and B-cell lymphoma, and potentiated Myc-driven lymphoma onset, dissemination and aggressiveness [94]. Interestingly, the Ptpn23+/−-derived tumours exhibited an unaltered remaining allele and maintained 50% of HD-PTP expression [94]. The analysis of human B-cell lymphoma and lung cancer samples as well as bioinformatic analysis of public data from tumour banks revealed frequent hemizygous PTPN23 deletion and HD-PTP down-regulation in many human tumours, which correlated with poor survival [94]. Together, our results identified HD-PTP/PTPN23 as a new haplo-insufficient tumour suppressor gene in mice and humans.

HD-PTP tumour suppressor mechanisms

Many HD-PTP physiological functions could be associated with its tumour suppressor activity, suggesting a wide range of mechanisms (see Figure 2). For instance, loss of HD-PTP had been extensively reported by many groups as a driver of cellular adhesion, migration and invasion, which is intimately linked to metastatic predisposition [29,80,81,9497]. In agreement with its ESCRT function, the endosomal trafficking of several receptors involved in cell migration and invasion is affected by HD-PTP depletion. For instance, it was shown that E-cadherins, the transmembrane proteins that form the adherens junction, failed to localize to the cell–cell junctions and rather accumulate in early endosomes upon loss of HD-PTP [81]. Importantly, we reported that loss of HD-PTP ESCRT function is associated with reduced integrin α5β1 degradation, which stimulated their expression levels, recycling and presence at the cell surface [29,94]. Upon HD-PTP depletion, the enhanced integrin stimulation promoted focal adhesion kinase (FAK) phosphorylation and signalling, a driver of cell survival and invasion in various cancers, including lymphoma [29,9499]. Consequently, HD-PTP heterozygous loss potentiated an integrin β1-dependent pro-survival and pro-invasive phenotype, which favoured Myc-driven lymphoma onset and dissemination in multiple mouse tissues [29,94]. In addition to FAK, loss of HD-PTP was reported to stimulate multiple pro-survival pathways associated with cancer susceptibility including pAKT, pSrc and pERK1/2 [29,81,94]. A previous report demonstrates that the Drosophila homologue of HD-PTP, Myopic, binds and represses the activity of the oncoprotein Yorkie, the homologue of the Yap transcriptional co-activator of the well-conserved Hippo tumour suppressor pathway [100]. The Hippo pathway prevents cell growth and promotes apoptosis by sequestering Yap into the cytoplasm, suggesting that loss of HD-PTP might favour Yap nuclear translocation and stimulates the transcription of several pro-growth regulators, but this function has not been confirmed in human samples [101]. Moreover, Miura et al. [102] showed that the loss of Myopic prevents cleavage of the EGFR cytoplasmic domain, which is mediated through a process controlled by the endocytic regulators. In addition, HD-PTP depletion reduced PDGFRβ degradation and enhanced NIH3T3 migration, proliferation and tumorigenicity upon PDGF stimulation [103]. Interestingly, the effect of HD-PTP depletion on accelerated cell transformation has been also reported. Indeed, hemizygous deletion of HD-PTP in non-transformed mouse embryonic fibroblasts (MEFs) correlates with reduced ARF (p14ARF) tumour suppressor levels [94]. In agreement with the fact that reduced ARF levels promote cellular immortalization, hemizygous loss of Ptpn23 accelerated the cell immortalization rate of primary MEFs [94]. In addition, loss of HD-PTP expression promoted focus formation and loss of contact inhibition in MEFs, and H-Rasv12-transformed immortalized MEFs showed an increase in the proliferation rate upon HD-PTP loss [94]. However, the mechanisms involved in these activities have not been identified.

HD-PTP potential tumour suppressor mechanisms.

Figure 2.
HD-PTP potential tumour suppressor mechanisms.

Several pathways regulated by HD-PTP are involved in cell survival, proliferation, immortalization and in cell adhesion, migration and invasion, and could be linked with its recently identified tumour suppressor activity. Yellow lines indicate pathways regulated by HD-PTP through unknown mechanisms; red lines indicate pathways identified in Drosophilia, but not confirmed in human samples; blue lines indicate pathways regulated through the HD-PTP ESCRT function.

Figure 2.
HD-PTP potential tumour suppressor mechanisms.

Several pathways regulated by HD-PTP are involved in cell survival, proliferation, immortalization and in cell adhesion, migration and invasion, and could be linked with its recently identified tumour suppressor activity. Yellow lines indicate pathways regulated by HD-PTP through unknown mechanisms; red lines indicate pathways identified in Drosophilia, but not confirmed in human samples; blue lines indicate pathways regulated through the HD-PTP ESCRT function.

Concluding remarks

As an ESCRT member responsible for the sorting and degradation of many cell surface receptors, it is likely that HD-PTP influences simultaneously multiple receptor-driven signalling cascades. Together, these up-regulated signalling pathways would contribute to HD-PTP tumour suppressor mechanisms. This major finding suggests that ESCRT decrease of function might represent a novel general post-translational tumour suppressor mechanism that should be further explored.

Abbreviations

     
  • ARF

    ADP-ribosylation factor

  •  
  • CHMP

    charged multi-vesicular body proteins

  •  
  • DiFMUP

    6,8-difluoro-4-methylumbelliferyl phosphate

  •  
  • EAP

    ELL-associated protein

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • ESCRT

    Endosomal Sorting Complexes Required for Transport

  •  
  • FAK

    focal adhesion kinase

  •  
  • HCC

    hepatocellular carcinoma

  •  
  • HD-PTP

    Histidine-Domain Protein Tyrosine Phosphatase

  •  
  • HIS

    histidine-rich domain

  •  
  • Hrs

    hepatocyte growth factor-regulated tyrosine kinase substrate

  •  
  • hVps

    human vacuolar protein sorting

  •  
  • LIP5

    LYST-interacting protein 5

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MEF

    mouse embryonic fibroblasts

  •  
  • MVB

    multi-vesicular bodies

  •  
  • NSCLC

    non-small-cell lung cancer

  •  
  • PRLs

    phosphatases of regenerating liver

  •  
  • PRR

    proline rich region

  •  
  • PTP

    protein tyrosine phosphatase

  •  
  • PTPN23

    protein tyrosine phosphatse non-receptor type 23

  •  
  • SDK1

    suppressor of K+ transport defect 1

  •  
  • STAM 1/2

    signal transducing adaptor molecule 1/2

  •  
  • TSG

    tumour suppressive gene

  •  
  • TSG101

    tumor susceptibility gene 101

  •  
  • UBAP1

    ubiquitin associated protein 1

  •  
  • Vps

    vacuolar protein sorting

Funding

This work was supported by grants from the Cancer Research Society (CRS) (to A.P.) and the Canadian Cancer Society Research Institute (CCSRI) [700525/702500 to A.P.]

Acknowledgments

We thank Dr Paola Blanchette for her critical reading of the manuscript.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Hanahan
,
D.
and
Weinberg
,
R.A.
(
2011
)
Hallmarks of cancer: the next generation
.
Cell
144
,
646
674
doi:
2
Mattissek
,
C.
and
Teis
,
D.
(
2014
)
The role of the endosomal sorting complexes required for transport (ESCRT) in tumorigenesis
.
Mol. Membr. Biol.
31
,
111
119
doi:
3
Schuh
,
A.L.
and
Audhya
,
A.
(
2014
)
The ESCRT machinery: from the plasma membrane to endosomes and back again
.
Crit. Rev. Biochem. Mol. Biol.
49
,
242
261
doi:
4
Schmidt
,
O.
and
Teis
,
D.
(
2012
)
The ESCRT machinery
.
Curr. Biol.
22
,
R116
R120
doi:
5
Hurley
,
J.H.
(
2015
)
ESCRTs are everywhere
.
EMBO J.
34
,
2398
2407
doi:
6
Saksena
,
S.
,
Sun
,
J.
,
Chu
,
T.
and
Emr
,
S.D.
(
2007
)
ESCRTing proteins in the endocytic pathway
.
Trends Biochem. Sci.
32
,
561
573
doi:
7
Asao
,
H.
,
Sasaki
,
Y.
,
Arita
,
T.
,
Tanaka
,
N.
,
Endo
,
K.
,
Kasai
,
H.
et al. 
(
1997
)
Hrs is associated with STAM, a signal-transducing adaptor molecule: its suppressive effect on cytokine-induced cell growth
.
J. Biol. Chem.
272
,
32785
32791
doi:
8
Babst
,
M.
,
Sato
,
T.K.
,
Banta
,
L.M.
and
Emr
,
S.D.
(
1997
)
Endosomal transport function in yeast requires a novel AAA-type ATPase, Vps4p
.
EMBO J.
16
,
1820
1831
doi:
9
Babst
,
M.
,
Katzmann
,
D.J.
,
Estepa-Sabal
,
E.J.
,
Meerloo
,
T.
and
Emr
,
S.D.
(
2002
)
Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting
.
Dev. Cell
3
,
271
282
doi:
10
Katzmann
,
D.J.
,
Babst
,
M.
and
Emr
,
S.D.
(
2001
)
Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I
.
Cell
106
,
145
155
doi:
11
Henne
,
W.M.
,
Buchkovich
,
N.J.
and
Emr
,
S.D.
(
2011
)
The ESCRT pathway
.
Dev. Cell
21
,
77
91
doi:
12
Raiborg
,
C.
,
Bremnes
,
B.
,
Mehlum
,
A.
,
Gillooly
,
D.J.
,
D'Arrigo
,
A.
,
Stang
,
E.
et al. 
(
2001
)
FYVE and coiled-coil domains determine the specific localisation of Hrs to early endosomes
.
J. Cell Sci.
114
(
Pt 12
),
2255
2263
PMID:
[PubMed]
13
Chu
,
T.
,
Sun
,
J.
,
Saksena
,
S.
and
Emr
,
S.D.
(
2006
)
New component of ESCRT-I regulates endosomal sorting complex assembly
.
J. Cell Biol.
175
,
815
823
doi:
14
Stefani
,
F.
,
Zhang
,
L.
,
Taylor
,
S.
,
Donovan
,
J.
,
Rollinson
,
S.
,
Doyotte
,
A.
et al. 
(
2011
)
UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting
.
Curr. Biol.
21
,
1245
1250
doi:
15
Wunderley
,
L.
,
Brownhill
,
K.
,
Stefani
,
F.
,
Tabernero
,
L.
and
Woodman
,
P.
(
2014
)
The molecular basis for selective assembly of the UBAP1-containing endosome-specific ESCRT-I complex
.
J. Cell Sci.
127
(
Pt 3
),
663
672
doi:
16
Ichioka
,
F.
,
Takaya
,
E.
,
Suzuki
,
H.
,
Kajigaya
,
S.
,
Buchman
,
V.L.
,
Shibata
,
H.
et al. 
(
2007
)
HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions
.
Arch. Biochem. Biophys.
457
,
142
149
doi:
17
Gahloth
,
D.
,
Levy
,
C.
,
Heaven
,
G.
,
Stefani
,
F.
,
Wunderley
,
L.
,
Mould
,
P.
et al. 
(
2016
)
Structural basis for selective interaction between the ESCRT regulator HD-PTP and UBAP1
.
Structure
24
,
2115
2126
doi:
18
Bache
,
K.G.
,
Raiborg
,
C.
,
Mehlum
,
A.
and
Stenmark
,
H.
(
2003
)
STAM and Hrs are subunits of a multivalent ubiquitin-binding complex on early endosomes
.
J. Biol. Chem.
278
,
12513
12521
doi:
19
Katzmann
,
D.J.
,
Stefan
,
C.J.
,
Babst
,
M.
and
Emr
,
S.D.
(
2003
)
Vps27 recruits ESCRT machinery to endosomes during MVB sorting
.
J. Cell Biol.
162
,
413
423
doi:
20
Lu
,
Q.
,
Hope
,
L.W.
,
Brasch
,
M.
,
Reinhard
,
C.
and
Cohen
,
S.N.
(
2003
)
TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation
.
Proc. Natl Acad. Sci. U.S.A.
100
,
7626
7631
doi:
21
Slagsvold
,
T.
,
Aasland
,
R.
,
Hirano
,
S.
,
Bache
,
K.G.
,
Raiborg
,
C.
,
Trambaiolo
,
D.
et al. 
(
2005
)
Eap45 in mammalian ESCRT-II binds ubiquitin via a phosphoinositide-interacting GLUE domain
.
J. Biol. Chem.
280
,
19600
19606
doi:
22
Babst
,
M.
,
Katzmann
,
D.J.
,
Snyder
,
W.B.
,
Wendland
,
B.
and
Emr
,
S.D.
(
2002
)
Endosome-associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body
.
Dev. Cell
3
,
283
289
doi:
23
Langelier
,
C.
,
von Schwedler
,
U.K.
,
Fisher
,
R.D.
,
De Domenico
,
I.
,
White
,
P.L.
,
Hill
,
C.P.
et al. 
(
2006
)
Human ESCRT-II complex and its role in human immunodeficiency virus type 1 release
.
J. Virol.
80
,
9465
9480
doi:
24
Teo
,
H.
,
Perisic
,
O.
,
González
,
B.
and
Williams
,
R.L.
(
2004
)
ESCRT-II, an endosome-associated complex required for protein sorting: crystal structure and interactions with ESCRT-III and membranes
.
Dev. Cell
7
,
559
569
doi:
25
Babst
,
M.
,
Wendland
,
B.
,
Estepa
,
E.J.
and
Emr
,
S.D.
(
1998
)
The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function
.
EMBO J.
17
,
2982
2993
doi:
26
Wittinger
,
M.
,
Vanhara
,
P.
,
El-Gazzar
,
A.
,
Savarese-Brenner
,
B.
,
Pils
,
D.
,
Anees
,
M.
et al. 
(
2011
)
hVps37A status affects prognosis and cetuximab sensitivity in ovarian cancer
.
Clin. Cancer Res.
17
,
7816
7827
doi:
27
Baldys
,
A.
and
Raymond
,
J.R.
(
2009
)
Critical role of ESCRT machinery in EGFR recycling
.
Biochemistry
48
,
9321
9323
doi:
28
Lobert
,
V.H.
,
Brech
,
A.
,
Pedersen
,
N.M.
,
Wesche
,
J.
,
Oppelt
,
A.
,
Malerod
,
L.
et al. 
(
2010
)
Ubiquitination of α5β1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
.
Dev. Cell
19
,
148
159
doi:
29
Kharitidi
,
D.
,
Apaja
,
P.M.
,
Manteghi
,
S.
,
Suzuki
,
K.
,
Malitskaya
,
E.
,
Roldan
,
A.
et al. 
(
2015
)
Interplay of endosomal pH and ligand occupancy in integrin α5β1 ubiquitination, endocytic sorting, and cell migration
.
Cell Rep.
13
,
599
609
doi:
30
Carlton
,
J.G.
,
Agromayor
,
M.
and
Martin-Serrano
,
J.
(
2008
)
Differential requirements for Alix and ESCRT-III in cytokinesis and HIV-1 release
.
Proc. Natl Acad. Sci. U.S.A.
105
,
10541
10546
doi:
31
Filimonenko
,
M.
,
Stuffers
,
S.
,
Raiborg
,
C.
,
Yamamoto
,
A.
,
Malerød
,
L.
,
Fisher
,
E.M.C.
et al. 
(
2007
)
Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease
.
J. Cell Biol.
179
,
485
500
doi:
32
Lee
,
J.-A.
,
Beigneux
,
A.
,
Ahmad
,
S.T.
,
Young
,
S.G.
and
Gao
,
F.-B.
(
2007
)
ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration
.
Curr. Biol.
17
,
1561
1567
doi:
33
Rusten
,
T.E.
,
Vaccari
,
T.
,
Lindmo
,
K.
,
Rodahl
,
L.M.W.
,
Nezis
,
I.P.
,
Sem-Jacobsen
,
C.
et al. 
(
2007
)
ESCRTs and Fab1 regulate distinct steps of autophagy
.
Curr. Biol.
17
,
1817
1825
doi:
34
Carlton
,
J.G.
and
Martin-Serrano
,
J.
(
2007
)
Parallels between cytokinesis and retroviral budding: a role for the ESCRT machinery
.
Science
316
,
1908
1912
doi:
35
Stoorvogel
,
W.
(
2015
)
Resolving sorting mechanisms into exosomes
.
Cell Res.
25
,
531
532
doi:
36
Colombo
,
M.
,
Moita
,
C.
,
van Niel
,
G.
,
Kowal
,
J.
,
Vigneron
,
J.
,
Benaroch
,
P.
et al. 
(
2013
)
Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles
.
J. Cell Sci.
126
(
Pt 24
),
5553
5565
doi:
37
Rusten
,
T.E.
and
Stenmark
,
H.
(
2009
)
How do ESCRT proteins control autophagy?
J. Cell Sci.
122
,
2179
2183
doi:
38
Loncle
,
N.
,
Agromayor
,
M.
,
Martin-Serrano
,
J.
and
Williams
,
D.W.
(
2015
)
An ESCRT module is required for neuron pruning
.
Sci. Rep.
5
,
8461
doi:
39
Jimenez
,
A.J.
,
Maiuri
,
P.
,
Lafaurie-Janvore
,
J.
,
Divoux
,
S.
,
Piel
,
M.
and
Perez
,
F.
(
2014
)
ESCRT machinery is required for plasma membrane repair
.
Science
343
,
1247136
doi:
40
Olmos
,
Y.
,
Hodgson
,
L.
,
Mantell
,
J.
,
Verkade
,
P.
and
Carlton
,
J.G.
(
2015
)
ESCRT-III controls nuclear envelope reformation
.
Nature
522
,
236
239
doi:
41
Saksena
,
S.
and
Emr
,
S.D.
(
2009
)
ESCRTs and human disease
.
Biochem. Soc. Trans.
37
(
Pt 1
),
167
172
doi:
42
Keating
,
D.J.
,
Chen
,
C.
and
Pritchard
,
M.A.
(
2006
)
Alzheimer's disease and endocytic dysfunction: clues from the Down syndrome-related proteins, DSCR1 and ITSN1
.
Ageing Res. Rev.
5
,
388
401
doi:
43
Yang
,
Y.
,
Hentati
,
A.
,
Deng
,
H.-X.
,
Dabbagh
,
O.
,
Sasaki
,
T.
,
Hirano
,
M.
et al. 
(
2001
)
The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis
.
Nat. Genet.
29
,
160
165
doi:
44
Stutts
,
M.J.
,
Canessa
,
C.M.
,
Olsen
,
J.C.
,
Hamrick
,
M.
,
Cohn
,
J.A.
,
Rossier
,
B.C.
et al. 
(
1995
)
CFTR as a cAMP-dependent regulator of sodium channels
.
Science
269
,
847
850
doi:
45
Chang
,
S.S.
,
Grunder
,
S.
,
Hanukoglu
,
A.
,
Rösler
,
A.
,
Mathew
,
P.M.
,
Hanukoglu
,
I.
et al. 
(
1996
)
Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1
.
Nat. Genet.
12
,
248
253
doi:
46
Botero-Velez
,
M.
,
Curtis
,
J.J.
and
Warnock
,
D.G.
(
1994
)
Brief report: Liddle's syndrome revisited—a disorder of sodium reabsorption in the distal tubule
.
N. Engl J. Med.
330
,
178
181
doi:
47
Freed
,
E.O.
(
2002
)
Viral late domains
.
J. Virol.
76
,
4679
4687
doi:
48
Pornillos
,
O.
,
Alam
,
S.L.
,
Rich
,
R.L.
,
Myszka
,
D.G.
,
Davis
,
D.R.
and
Sundquist
,
W.I.
(
2002
)
Structure and functional interactions of the Tsg101 UEV domain
.
EMBO J.
21
,
2397
2406
doi:
49
Jiang
,
Y.
,
Ou
,
Y.
and
Cheng
,
X.
(
2013
)
Role of TSG101 in cancer
.
Front. Biosci.
18
,
279
288
PMID:
[PubMed]
50
Toyoshima
,
M.
,
Tanaka
,
N.
,
Aoki
,
J.
,
Tanaka
,
Y.
,
Murata
,
K.
,
Kyuuma
,
M.
et al. 
(
2007
)
Inhibition of tumor growth and metastasis by depletion of vesicular sorting protein Hrs: its regulatory role on E-cadherin and β-catenin
.
Cancer Res.
67
,
5162
5171
doi:
51
Oh
,
K.B.
,
Stanton
,
M.J.
,
West
,
W.W.
,
Todd
,
G.L.
and
Wagner
,
K.-U.
(
2007
)
Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation
.
Oncogene
26
,
5950
5959
doi:
52
Liu
,
R.-T.
,
Huang
,
C.-C.
,
You
,
H.-L.
,
Chou
,
F.F.
,
Hu
,
C.-C.A.
,
Chao
,
F.-P.
et al. 
(
2002
)
Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas
.
Oncogene
21
,
4830
4837
doi:
53
Ma
,
X.R.
,
Edmund Sim
,
U.H.
,
Pauline
,
B.
,
Patricia
,
L.
and
Rahman
,
J.
(
2008
)
Overexpression of WNT2 and TSG101 genes in colorectal carcinoma
.
Trop. Biomed.
25
,
46
57
PMID:
[PubMed]
54
Nikolova
,
D.N.
,
Doganov
,
N.
,
Dimitrov
,
R.
,
Angelov
,
K.
,
Low
,
S.K.
,
Dimova
,
I.
et al. 
(
2009
)
Genome-wide gene expression profiles of ovarian carcinoma: Identification of molecular targets for the treatment of ovarian carcinoma
.
Mol. Med. Rep.
2
,
365
384
PMID:
[PubMed]
55
Xu
,
Z.
,
Liang
,
L.
,
Wang
,
H.
,
Li
,
T.
and
Zhao
,
M.
(
2003
)
HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein
.
Biochem. Biophys. Res. Commun.
311
,
1057
1066
doi:
56
Xiao
,
B.
,
Fan
,
S.
,
Zeng
,
Z.
,
Xiong
,
W.
,
Cao
,
L.
,
Yang
,
Y.
et al. 
(
2006
)
Purification of novel UBAP1 protein and its decreased expression on nasopharyngeal carcinoma tissue microarray
.
Protein Expr. Purif.
47
,
60
67
doi:
57
Li
,
J.
,
Belogortseva
,
N.
,
Porter
,
D.
and
Park
,
M.
(
2008
)
Chmp1a functions as a novel tumor suppressor gene in human embryonic kidney and ductal pancreatic tumor cells
.
Cell Cycle
7
,
2886
2893
doi:
58
Liao
,
Z.
,
Thomas
,
S.N.
,
Wan
,
Y.
,
Lin
,
H.H.
,
Ann
,
D.K.
and
Yang
,
A.J.
(
2013
)
An internal standard-assisted synthesis and degradation proteomic approach reveals the potential linkage between VPS4B depletion and activation of fatty acid β-oxidation in breast cancer cells
.
Int. J. Proteomics
2013
,
1
13
doi:
59
Lin
,
H.H.
,
Li
,
X.
,
Chen
,
J.-L.
,
Sun
,
X.
,
Cooper
,
F.N.
,
Chen
,
Y.-R.
et al. 
(
2012
)
Identification of an AAA ATPase VPS4B-dependent pathway that modulates epidermal growth factor receptor abundance and signaling during hypoxia
.
Mol. Cell. Biol.
32
,
1124
1138
doi:
60
Liu
,
Y.
,
Lv
,
L.
,
Xue
,
Q.
,
Wan
,
C.
,
Ni
,
T.
,
Chen
,
B.
et al. 
(
2013
)
Vacuolar protein sorting 4B, an ATPase protein positively regulates the progression of NSCLC via promoting cell division
.
Mol. Cell. Biochem.
381
,
163
171
doi:
61
Toyooka
,
S.-i.
,
Ouchida
,
M.
,
Jitsumori
,
Y.
,
Tsukuda
,
K.
,
Sakai
,
A.
,
Nakamura
,
A.
et al. 
(
2000
)
HD-PTP: a novel protein tyrosine phosphatase gene on human chromosome 3p21.3
.
Biochem. Biophys. Res. Commun.
278
,
671
678
doi:
62
Zhai
,
Q.
,
Landesman
,
M.B.
,
Robinson
,
H.
,
Sundquist
,
W.I.
and
Hill
,
C.P.
(
2011
)
Structure of the Bro1 domain protein BROX and functional analyses of the ALIX Bro1 domain in HIV-1 budding
.
PLoS ONE
6
,
e27466
doi:
63
Odorizzi
,
G.
(
2006
)
The multiple personalities of Alix
.
J. Cell Sci.
119
(
Pt 15
),
3025
3032
doi:
64
Fisher
,
R.D.
,
Chung
,
H.-Y.
,
Zhai
,
Q.
,
Robinson
,
H.
,
Sundquist
,
W.I.
and
Hill
,
C.P.
(
2007
)
Structural and biochemical studies of ALIX/AIP1 and its role in retrovirus budding
.
Cell
128
,
841
852
doi:
65
Zhou
,
X.
,
Pan
,
S.
,
Sun
,
L.
,
Corvera
,
J.
,
Lee
,
Y.-C.
,
Lin
,
S.-H.
et al. 
(
2009
)
The CHMP4b- and Src-docking sites in the Bro1 domain are autoinhibited in the native state of Alix
.
Biochem. J.
418
,
277
284
doi:
66
Pashkova
,
N.
,
Gakhar
,
L.
,
Winistorfer
,
S.C.
,
Sunshine
,
A.B.
,
Rich
,
M.
,
Dunham
,
M.J.
et al. 
(
2013
)
The yeast Alix homolog Bro1 functions as a ubiquitin receptor for protein sorting into multivesicular endosomes
.
Dev. Cell
25
,
520
533
doi:
67
Alonso
,
A.
,
Sasin
,
J.
,
Bottini
,
N.
,
Friedberg
,
I.
,
Friedberg
,
I.
,
Osterman
,
A.
et al. 
(
2004
)
Protein tyrosine phosphatases in the human genome
.
Cell
117
,
699
711
doi:
68
Andersen
,
J.N.
,
Mortensen
,
O.H.
,
Peters
,
G.H.
,
Drake
,
P.G.
,
Iversen
,
L.F.
,
Olsen
,
O.H.
et al. 
(
2001
)
Structural and evolutionary relationships among protein tyrosine phosphatase domains
.
Mol. Cell. Biol.
21
,
7117
7136
doi:
69
Rechsteiner
,
M.
and
Rogers
,
S.W.
(
1996
)
PEST sequences and regulation by proteolysis
.
Trends Biochem. Sci.
21
,
267
271
doi:
70
Rechsteiner
,
M.
(
1990
)
PEST sequences are signals for rapid intracellular proteolysis
.
Semin. Cell Biol.
1
,
433
440
PMID:
[PubMed]
71
Doyotte
,
A.
,
Mironov
,
A.
,
McKenzie
,
E.
and
Woodman
,
P.
(
2008
)
The Bro1-related protein HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis
.
Proc. Natl Acad. Sci. U.S.A.
105
,
6308
6313
doi:
72
Parkinson
,
M.D.J.
,
Piper
,
S.C.
,
Bright
,
N.A.
,
Evans
,
J.L.
,
Boname
,
J.M.
,
Bowers
,
K.
et al. 
(
2015
)
A non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I
.
Biochem. J.
471
,
79
88
doi:
73
Ali
,
N.
,
Zhang
,
L.
,
Taylor
,
S.
,
Mironov
,
A.
,
Urbé
,
S.
and
Woodman
,
P.
(
2013
)
Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB
.
Curr. Biol.
23
,
453
461
doi:
74
Agromayor
,
M.
,
Soler
,
N.
,
Caballe
,
A.
,
Kueck
,
T.
,
Freund
,
S.M.
,
Allen
,
M.D.
et al. 
(
2012
)
The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain
.
Structure
20
,
414
428
doi:
75
Gingras
,
M.-C.
,
Zhang
,
Y.L.
,
Kharitidi
,
D.
,
Barr
,
A.J.
,
Knapp
,
S.
,
Tremblay
,
M.L.
et al. 
(
2009
)
HD-PTP is a catalytically inactive tyrosine phosphatase due to a conserved divergence in its phosphatase domain
.
PLoS ONE
4
,
e5105
doi:
76
Barr
,
A.J.
,
Ugochukwu
,
E.
,
Lee
,
W.H.
,
King
,
O.N.F.
,
Filippakopoulos
,
P.
,
Alfano
,
I.
et al. 
(
2009
)
Large-scale structural analysis of the classical human protein tyrosine phosphatome
.
Cell
136
,
352
363
doi:
77
Flint
,
A.J.
,
Tiganis
,
T.
,
Barford
,
D.
and
Tonks
,
N.K.
(
1997
)
Development of ‘substrate-trapping’ mutants to identify physiological substrates of protein tyrosine phosphatases
.
Proc. Natl Acad. Sci. U.S.A.
94
,
1680
1685
doi:
78
Tonks
,
N.K.
(
2006
)
Protein tyrosine phosphatases: from genes, to function, to disease
.
Nat. Rev. Mol. Cell Biol.
7
,
833
846
doi:
79
Wishart
,
M.J.
and
Dixon
,
J.E.
(
1998
)
Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains
.
Trends Biochem. Sci.
23
,
301
306
doi:
80
Chen
,
D.-Y.
,
Li
,
M.-Y.
,
Wu
,
S.-Y.
,
Lin
,
Y.-L.
,
Tsai
,
S.-P.
,
Lai
,
P.-L.
et al. 
(
2012
)
The Bro1-domain-containing protein Myopic/HDPTP coordinates with Rab4 to regulate cell adhesion and migration
.
J. Cell Sci.
125
(
Pt 20
),
4841
4852
doi:
81
Lin
,
G.
,
Aranda
,
V.
,
Muthuswamy
,
S.K.
and
Tonks
,
N.K.
(
2011
)
Identification of PTPN23 as a novel regulator of cell invasion in mammary epithelial cells from a loss-of-function screen of the ‘PTP-ome’
.
Genes Dev.
25
,
1412
1425
doi:
82
Blanchetot
,
C.
,
Chagnon
,
M.
,
Dube
,
N.
,
Halle
,
M.
and
Tremblay
,
M.L.
(
2005
)
Substrate-trapping techniques in the identification of cellular PTP targets
.
Methods
35
,
44
53
doi:
83
Zhang
,
H.
,
Kozlov
,
G.
,
Li
,
X.
,
Wu
,
H.
,
Gulerez
,
I.
and
Gehring
,
K.
(
2017
)
PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3
.
Sci. Rep.
7
,
48
doi:
84
Ji
,
L.
,
Minna
,
J.D.
and
Roth
,
J.A.
(
2005
)
3p21.3 tumor suppressor cluster: prospects for translational applications
.
Future Oncol.
1
,
79
92
doi:
85
Imreh
,
S.
,
Klein
,
G.
and
Zabarovsky
,
E.R.
(
2003
)
Search for unknown tumor-antagonizing genes
.
Genes Chromosomes Cancer
38
,
307
321
doi:
86
Senchenko
,
V.N.
,
Liu
,
J.
,
Loginov
,
W.
,
Bazov
,
I.
,
Angeloni
,
D.
,
Seryogin
,
Y.
et al. 
(
2004
)
Discovery of frequent homozygous deletions in chromosome 3p21.3 LUCA and AP20 regions in renal, lung and breast carcinomas
.
Oncogene
23
,
5719
5728
doi:
87
Braga
,
E.
,
Senchenko
,
V.
,
Bazov
,
I.
,
Loginov
,
W.
,
Liu
,
J.
,
Ermilova
,
V.
et al. 
(
2002
)
Critical tumor-suppressor gene regions on chromosome 3P in major human epithelial malignancies: allelotyping and quantitative real-time PCR
.
Int. J. Cancer
100
,
534
541
doi:
88
Hesson
,
L.B.
,
Cooper
,
W.N.
and
Latif
,
F.
(
2007
)
Evaluation of the 3p21.3 tumour-suppressor gene cluster
.
Oncogene
26
,
7283
7301
PMID:
[PubMed]
89
Angeloni
,
D.
(
2007
)
Molecular analysis of deletions in human chromosome 3p21 and the role of resident cancer genes in disease
.
Brief. Funct. Genomics Proteomics
6
,
19
39
doi:
90
Qian
,
J.
,
Yang
,
J.
,
Zhang
,
X.
,
Zhang
,
B.
,
Wang
,
J.
,
Zhou
,
M.
et al. 
(
2001
)
Isolation and characterization of a novel cDNA, UBAP1, derived from the tumor suppressor locus in human chromosome 9p21-22
.
J. Cancer Res. Clin. Oncol.
127
,
613
618
doi:
91
Cao
,
L.
,
Zhang
,
L.
,
Ruiz-Lozano
,
P.
,
Yang
,
Q.
,
Chien
,
K.R.
,
Graham
,
R.M.
et al. 
(
1998
)
A novel putative protein-tyrosine phosphatase contains a BRO1-like domain and suppresses Ha-ras-mediated transformation
.
J. Biol. Chem.
273
,
21077
21083
doi:
92
Tanaka
,
K.
,
Kondo
,
K.
,
Kitajima
,
K.
,
Muraoka
,
M.
,
Nozawa
,
A.
and
Hara
,
T.
(
2013
)
Tumor-suppressive function of protein-tyrosine phosphatase non-receptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA
.
J. Biol. Chem.
288
,
23990
23999
doi:
93
Gingras
,
M.-C.
,
Kharitidi
,
D.
,
Chenard
,
V.
,
Uetani
,
N.
,
Bouchard
,
M.
,
Tremblay
,
M.L.
et al. 
(
2009
)
Expression analysis and essential role of the putative tyrosine phosphatase His-domain-containing protein tyrosine phosphatase (HD-PTP)
.
Int. J. Dev. Biol.
53
,
1069
1074
doi:
94
Manteghi
,
S.
,
Gingras
,
M.-C.
,
Kharitidi
,
D.
,
Galarneau
,
L.
,
Marques
,
M.
,
Yan
,
M.
et al. 
(
2016
)
Haploinsufficiency of the ESCRT component HD-PTP predisposes to cancer
.
Cell Rep.
15
,
1893
1900
doi:
95
Castiglioni
,
S.
,
Maier
,
J.A.M.
and
Mariotti
,
M.
(
2007
)
The tyrosine phosphatase HD-PTP: a novel player in endothelial migration
.
Biochem. Biophys. Res. Commun.
364
,
534
539
doi:
96
Mariotti
,
M.
,
Castiglioni
,
S.
,
Garcia-Manteiga
,
J.M.
,
Beguinot
,
L.
and
Maier
,
J.A.M.
(
2009
)
HD-PTP inhibits endothelial migration through its interaction with Src
.
Int. J. Biochem. Cell Biol.
41
,
687
693
doi:
97
Mariotti
,
M.
,
Castiglioni
,
S.
and
Maier
,
J.A.M.
(
2009
)
Inhibition of T24 human bladder carcinoma cell migration by RNA interference suppressing the expression of HD-PTP
.
Cancer Lett.
273
,
155
163
doi:
98
Alanko
,
J.
,
Mai
,
A.
,
Jacquemet
,
G.
,
Schauer
,
K.
,
Kaukonen
,
R.
,
Saari
,
M.
et al. 
(
2015
)
Integrin endosomal signalling suppresses anoikis
.
Nat. Cell Biol.
17
,
1412
1421
doi:
99
Desgrosellier
,
J.S.
and
Cheresh
,
D.A.
(
2010
)
Integrins in cancer: biological implications and therapeutic opportunities
.
Nat. Rev. Cancer
10
,
9
22
doi:
100
Gilbert
,
M.M.
,
Tipping
,
M.
,
Veraksa
,
A.
and
Moberg
,
K.H.
(
2011
)
A screen for conditional growth suppressor genes identifies the Drosophila homolog of HD-PTP as a regulator of the oncoprotein Yorkie
.
Dev. Cell
20
,
700
712
doi:
101
Yu
,
F.-X.
,
Zhao
,
B.
and
Guan
,
K.-L.
(
2015
)
Hippo pathway in organ size control, tissue homeostasis, and cancer
.
Cell
163
,
811
828
doi:
102
Miura
,
G.I.
,
Roignant
,
J.-Y.
,
Wassef
,
M.
and
Treisman
,
J.E.
(
2008
)
Myopic acts in the endocytic pathway to enhance signaling by the Drosophila EGF receptor
.
Development
135
,
1913
1922
doi:
103
Ma
,
H.
,
Wardega
,
P.
,
Mazaud
,
D.
,
Klosowska-Wardega
,
A.
,
Jurek
,
A.
,
Engström
,
U.
et al. 
(
2015
)
Histidine-domain-containing protein tyrosine phosphatase regulates platelet-derived growth factor receptor intracellular sorting and degradation
.
Cell. Signal.
27
,
2209
2219
doi: