The role of receptor‐type protein tyrosine phosphatases in cancer

Receptor‐type protein tyrosine phosphatases (RPTPs), Class I protein tyrosine phosphatases, are involved in human tumor cell proliferation, apoptosis, migration, and invasion through reversible phosphorylation of tyrosine residues. This review summarizes the expression and role of RPTPs in cancer and illustrates the signaling pathway mechanisms of effecting oncogenesis, tumor progression, prognosis, and angiogenesis, so as to provide more effective targets for gene therapy of related cancers.

in epithelial-mesenchymal transition (EMT) and tumor metastasis. 8 Here, this review trends to summarize the functions and mechanisms of the RPTP subfamilies in cancers.
2 | R1/R6 SUBFAMILY PTPRC, also named CD45, is the only R1/R6 subfamily member 4 and is a prototypical receptor-like PTP. 9 There are a C-terminal tail of 79 amino acids, a putative wedge-like domain, and two tandem PTP domains (D1 and D2) in its ICD. 10  . Only the M2 mutant was able to restore the interaction of CD45 with its specific substrates, demonstrating the catalytic function of D1 domain. 11 The D2 domain functioned to stabilize the activity of CD45 together with D1; however, the D2 domain itself did not have a catalytic activity. 12 The ECD is consisted of five regions: an extended N-terminal region, three membrane-proximal domains, a cysteine-rich globular domain, and multiple N-linked glycosylation sites. 10 The extended N-terminal region contains many O-linked glycosylation sites. 9,10 The membrane-proximal domains are belong to type-III fibronectin (FNIII) domain family. 13 Between variable N-terminal domains and the three FNIII domains is a cysteine-rich globular domain. The N-linked glycosylation sites exist in both the cysteine-rich and FNIII domains. 9 During cell differentiation and activation, PTPRC can be modulated by glycosylation, so as to regulate T-cell receptor signaling, T-cell migration, cell survival, and apoptosis. 14 It is reported by Osamu Suzuki et al. that reducing its N-glycans or O-glycans prevented the interaction between PTPRC and galectin-1, resulting in the inhibition of cell death in human diffuse large B-cell lymphoma. 15 Ligandinduced dimerization is also a possible method for phosphatase activity regulation. Although a specific ligand for PTPRC has not been identified, in addition to galectin-1 mentioned above, pUL11 generated in response to cytomegalovirus infection, and placental protein 14 generated in the first or second trimester of pregnancy are possible ligands. 16 PTPRC is commonly found in leukocytes and is also called as leukocyte common antigen (LCA). For bone marrow-derived mast cells, PTPRC deficiency leads to increased phosphorylation of inhibitory LYN and severe attenuation of degranulation and cytokine secretion in response to Ag-triggered FcεR1-mediated activation. 17 In macrophages, PTPRC maintains β2 integrin-mediated adhesion, which is critical for macrophage maturation and function. 18  rapid differentiation of monocytic myeloid-derived suppressor cells (M-MDSCs) to tumor-associated macrophages (TAMs), thus resulting in rapid tumor progression and metastasis. 19 In addition, lacking PTPRC has a phenotype of severe combined immunodeficiency (SCID) and low T-cell numbers, which is strikingly similar to that of SCID patients, 20 demonstrating the importance of PTPRC in lymphocyte maturation and signal transduction. Moreover, PTPRC dephosphorylates p56 LCK , a kind of SRC-family kinases (SFKs), to regulate T-cell immune responses. 21 It dephosphorylates p56 LCK at the Y505 site, allows p56 LCK to be activated by trans-phosphorylating the Y394 site, and promotes antigen recognition of pathogens and malignant tumors by enhancing TCR signaling in the immune system. 21 PTPRC also negatively regulates the JAK/STAT signaling pathway by JAKs dephosphorylation. It is reported that downregulation of PTPRC expression promotes the proliferation of the T-cell acute lymphoblastic leukemia by enhancing the sensitivity of T cell to cytokines and following by an activation of JAK/STAT signaling pathway. 22 3 | R2A SUBFAMILY R2A subfamily, as known as LAR subfamily, is composed of three vertebrate homologs: PTPRF, PTPRS, and PTPRD. Their ECDs mainly contain three immunoglobulin-like (Ig-like) domains and four to eight FNIII domains, which are resemble with cell adhesion molecules (CAMs)-immunoglobulin (Ig) superfamily. 23 Heparan sulfate proteoglycans (HSPGs) are R2A subfamily heterotypic ligands. It is reported that HSPG agrin heparan sulfate chains and collagen XVIII directly regulated PTPRS activity. 24 However, Jae-hyuk Yi et al. found that the binding sites for PTPRS were actually on neurons and were not heparan sulfate chains in normal mouse brain. 25 HSPGs Syndecan directly binds to PTPRF and promotes PTPRF signal transduction in motor axon guidance, 26 while HSPGs Dallylike inhibits PTPRF activity. 27 PTPRS mainly plays a role of tumor suppression. It is reported that PTPRS induces the dephosphorylation of EGFR 28 and causes PI3Ks inactivated so as to dephosphorylate the phosphatidylinositol on the 3 0 -hydroxyl group in the PI3K/EGFR pathway. In head and neck squamous cell carcinoma (HNSCC), the high phosphorylation level of EGFR is associated with the low expression of PTPRS and the deletion of PTPRS can activate EGFR/PI3K pathway. 29 Moreover, in hepatocellular carcinoma (HCC), EGFR/PI3K pathway is reported to be involved in the EMT progression through a mechanism of DNA hypermethylation in the PTPRS promoter at its 5 0 -upstream region. 30 In colorectal cancer (CRC), PTPRS negatively regulates the activity of ERK (ERK1 and ERK2), the phosphorylation of which is a direct indicator of RAS pathway activation in promoting tumor cell growth and angiogenesis. 31 PTPRD is an essential tumor-suppressor gene that its deletion, as well as mutation, copy number loss, and hypermethylation, can lead to various cancers. 32 Among 31 patients with metastatic cutaneous squamous cell carcinoma, 37% is found deletion at the PTPRD locus. 33 In a study of glioblastoma multiforme (GBM) and malignant melanoma, focal deletions of PTPRD on chromosome 9p23-24.1 is present in 14% of the GBM samples and the somatic missense mutations of PTPRD is 12% of the melanoma tumor samples. 34 Additionally, in a study of limited number of Ewing sarcoma (ES) patients, three cases in eight ES samples is identified as germline mutations of PTPRD 35 and a 14-year-old male ES patient of germline intragenic deletion of PTPRD is presented in another case report. 36 The hypermethylation of PTPRD promoter is favorable for HCC development. The PTPRD promoter is found hypermethylated in 6/27 tumor samples, resulting in downregulation of PTPRD expression. 37 Because PTPRD dephosphorylates STAT3 at Tyr705 site, then it prevents phosphorylated STAT3 from translocating into nucleus to downregulate the expression of MMP-2 and MMP-9, and results in the inhibition of proliferation and angiogenesis of tumor cells. 32 PTPRD can also negatively regulate CXCL8, a chemokine secreted by tumor cells in an autocrine or paracrine manner, so as to suppress angiogenesis. This mechanism is also applicable in gastric cancers (GCs). 32,38 In a murine tumor model developed by
The Ig-like domains and FNIII domains of ECD in R2B subfamily are similar to those in R2A subfamily. But there is a MAM domain in the ECD of R2B subfamily. 4 The MAM domain contributes to the respective homophilic adhesion of PTPRK and PTPRM, and it also prevents PTPRK from interacting with PTPRM, even though PTPRK is structurally similar to PTPRM. 43 This homophilic adhesion would also result in dimerization of tyrosine phosphatases, with the potential to affect the activity of phosphatases. 44 PTPRT functions as an anti-oncogene to inhibit tumor growth. It is reported that PTPRT disrupted the microtubule dynamics, leading to a low proliferation rate and a high apoptosis rate in breast cancer (BRCA). 45 According to the TCGA data, high PTPRT expression is associated with a longer survival time in BRCA. 45 In addition, PTPRT is considered to be the most frequently mutated RPTPs in human cancers including CRCs (27% mutation frequency), GCs (17% mutation frequency), and lung cancers (18% mutation frequency). 3 It was found that the mutated PTPRT (A1022E), which is stable expressed in the serum-dependent HNSCC cell line, caused an enhanced phosphorylation of STAT3 at the Y705 site, while mutated PTPRT (P497T) in the FNIII domain did not affect STAT3 status. 46  PTPRK is a typical tumor suppressor. Its methylation is often detected in adult acute lymphoblastic leukemia (ALL), which can promote tumor cell proliferation and inhibit apoptosis. 54 Knockdown of PTPRK potentiates the CD133-AKT pathway in colon cancer. 55 In NSCLC, knocking down endogenous PTPRK in H1299 and A549 cells leads to enhanced cell invasion and increases phosphorylation level of STAT3 at Tyr705 site. 56 In addition, PTPRK silencing also activates β-catenin in Wnt pathway and affects E-cadherin/β-catenin complex stabilization at the cell membrane to promote EMT and cell-cell adhesion deletion, demonstrating PTPRK to be a tumor suppressor. 57 PTPRU is a phosphatase without catalytic activity. However, its D2 domain can recruit substrates for the dephosphorylation via the D1 domain of PTPRK. Furthermore, PTPRU deletion causes a reduction of the phosphorylation level of P120, which is the PTPRK substrate. 58 PTPRU is considered to be a tumor suppressor in CRC. It binds the Ecadherin/β-catenin complex to the cytoskeleton tightly and downregulates the signaling activity of β-catenin to inhibit CRC development and cell proliferation. 59 However, in GC, endogenous PTPRU knockdown using lentivirus-delivered specific shRNA inhibits the cell growth and motility and also represses the transcriptional activity of β-catenin. 60 A similar result has also been reported in glioma, 61 62 It is worth mentioning PTPRJ (also called CD148), whose ligands include thrombospondin-1 (TSP1) 63 and syndecan-2. 64 Compared with CD148 WT A431D cells (human epidermal cancer cells), the CD148 knockdown abolished the ability of TSP1 to inhibit cell proliferation, suggesting that TSP1 interacts with CD148 to inhibit epidermal cell growth and angiogenesis. 63 Syndecan-2 is a novel ligand of PTPRJ. It binds to PTPRJ and transduces signals from PTPRJ to β1 integrins, affecting the cell adhesion to the extracellular matrix. 64 PTPRB is high-expressed in both CRC and CCa. It induces EMT and promotes the proliferation, migration, and invasion of tumor cells. 65,66 In NSCLC, PTPRB acts as a tumor suppressor, the phosphorylation level of SRC at Y418 site is decreased in PTPRB overexpressed cells. 67 In HCC, PTPRB is a direct target of miR-665 and is negatively regulated by miR-665, promoting proliferation, migration, and invasion of HCC cells through Hippo signaling pathway. 68  to be a key driver gene of angiosarcoma. 69 PTPRH is considered as an oncogene in CRC for its high expression level. 70 But some other researchers raised observation that the DNA methylation levels of PTPRH promoter in CRC were significantly higher than that in normal intestinal mucosa tissues, suggesting that the low expression of PTPRH is closely related to CRC development. 71 PTPRO is considered as a potential tumor suppressor gene. It is reported that PTPRO silence caused by methylation of the CpG island encompassing the exon1 is found in HCC. 72 The hypermethylation of PTPRO promoter is also found in primary BRCA tissues and positively associated with bad outcome such as poorly differentiated histology and depth of invasion. 73 When the methylation of PTPRO is inhibited by 5-azacytidine in the BRCA cells, the ErbB2-induced cell growth and transformation are reduced, because PTPRO can dephosphorylate ErbB2 (HER2) at Y1248 site to negatively regulate the activity of AKT and ERK. 74 In CRC, PTPRO dramatically dephosphorylates EGFR (HER1) at Y845 site through a direct inactivation of SRC kinase activity, which leads to the dephosphorylation of ERK1/2 in MAPK pathway, indicating that PTPRO inactivates EGFR/MAPK pathway by downregulating SRC kinase activity. 75 Moreover, PTPRO dephosphorylates STAT3 at Y705 through inactivated JAK2 at S727 site through inactivated PI3K to exert the tumor-suppressive ability in HCC. 76 In addition, PTPRO is found a role in oxidative stress mechanism that overexpressing PTPRO increases ROS production and promotes apoptosis through TLR4/NF-κB pathway. 77 PTPRJ plays different roles depending on the cancer type. It is regulated by complex mechanisms. The deletion of PTPRJ promotes the development of GC, lung cancer, BRCA, 78 81 It is reported that PTPRJ inhibits the malignant transformation of GC by dephosphorylating EGFR at Y1173, Y1068, and Y1092 sites and by inhibiting the MEK/ERK and PI3K/AKT pathways. 83 Moreover, in a CCa cell line, PTPRJ negatively regulates the activation of the JAK1/STAT3 pathway and PTPRJ overexpression reduces BAX and increases BCL-2, which are downstream effectors of STAT3. 84 However, phosphorylated PTPRJ binds to the SH2 domain of SRC, resulting in a dephosphorylation of SRC at Y529 residue and leading to a phosphorylation of SRC at Y418 residue. PTPRJ then activates the SRC pathway to promote tumor-associated angiogenesis. 85 PTPRQ is the only R3 subfamily member that has low ability against phosphotyrosine but is active against phosphatidylinositol phosphates, because there is a replacement of aspartic acid by glutamic acid in the WPD loop of its PTP domain. 86 The PIPase activity of PTPRQ dramatically reduces proliferative rates of GBM cells and promotes GBM cells apoptosis. 87 However, PTPRQ is highly expressed in CRC, indicating that PTPRQ is an oncogene. So PTPRQ have dual functions, it is either a tumor suppressor and is also considered as the oncogene in many human cancers. 88 6 | R4 SUBFAMILY PTPRA and PTPRE are R4 subfamily members. They contain short but highly glycosylated segments without CAM homology domains in their ECDs.
PTPRA is the only member whose D2 domain is active in RPTPs. 5 It is highly expressed in many primary tumors. For example, PTPRA is highly expressed in human oral squamous cell carcinoma, and its expression level is associated with tumor dedifferentiation and stoma recruitment. 89 In BRCA of the HER2-positive subtype, a decrease of AKT phosphorylation (Ser473) is caused by PTPRA contributing to tumor maintenance. 90 PTPRA knockdown reduces the degradation of ECM and partly inhibits the MDA-MB-231 cell invasion, suggesting that PTPRA promotes the invasion of tumor cells. 91 Moreover, the downregulation of circPTPRA is associated with metastatic disease and a shorter survival time in patients with NSCLC. The circPTPRA sponges miR-96-5p, an oncogenic miRNA, in NSCLC mouse xenograft model so as to suppress EMT via the miR-96-5p/RASSF8/E-cadherin axis. 92 What is more interesting, PTPRA functionally regulates ROS signal transduction. The growing evidences suggest that ROS may have two-side functions depending on concentration that H(2)O(2) of low to moderate concentration suppresses the phosphorylation of PTPRA at Tyr789 site. 93 As a positive regulator of SFKs, RPTPA regulates SRC signaling pathway in cancer development. 94 In addition, PTPRA has a function of setting the threshold for the forcedependent formation of adhesion sites mediated by SFK/MACK. It is reported to affect colon cancer cells to adhere to pliable surfaces and to invade into the stroma of the chicken chorioallantoic membrane. 95 PTPRE is a tyrosine phosphatase and it promotes ErbB2-induced mammary tumorigenesis. The phosphorylation of PTPRE at Y695 site is induced by ErbB2, leading to an activation of c-SRC. 96 In addition, PTPRE can also be regulated by the activation of ERK1/2 and through AKT pathways. 97 7 | R5 SUBFAMILY R5 subfamily members are PTPRZ1 and PTPRG. Their ICDs possess tandem PTP domains, and their ECDs contain a single FNIII domain and an N-terminal carbonic anhydrase-like domain, which characterized as a hydrophobic binding pocket for a heterophilic ligand. 5 The activity of PTPRZ1 could be inhibited by Pleiotrophin (PTN).
It is reported in a "head-to-toe dimerization" model that D2 masks the catalytic site of D1, and D2 deletion or its mutation abolished the inhibitory effect of PTN on PTPRZ1, indicating that PTN affected the activity of PTPRZ1 through altering the dimerization. 98 PTPRZ1 can be found high expression level in human primary and metastatic melanomas, 99 CCa, 100 and GBM. 101 The high expression level of PTPRZ1 is also associated with chronic oxidative stress.
PTPRZ1 is found increased in a renal carcinoma (RCC) model induced by oxidative renal tubular damage, and the β-catenin pathway is activated without Wnt signaling. 102 In addition, pleiotrophin (PTN) binds to PTPRZ1 and increases tyrosine phosphorylation status of calmodulin (CaM) in SCLC cells, affecting angiogenesis and tumor growth. 103 Moreover, it is reported that TAMs secrete abundant PTN to promote malignant growth of glioblastoma by binding to PTPRZ1. 104 PTPRG-AS1 is overexpressed in epithelial ovarian cancer (EOC) tissues and acts as an oncogene. 105 It downregulates the expression level of miR-545-3p and thus increases HDAC4 to aggravate the malignancy of EOC. 106 PTPRG-AS1 has a similar effect in HCC. It negatively regulates miR-199a-3p expression and thus increases YWHAG to promote the metastasis of HCC. 107 In BRCA, PTPRG significantly inhibits oncogenesis, it upregulates p21 (cip) and p27 (kip) expression levels through the ERK1/2 pathway to delay cell cycle re-entry. 108 Moreover, miR-19b can negatively regulate PTPRG expression. 109 In nasopharyngeal carcinoma, PTPRG dephosphorylates EGFR to inactivate the PI3K/AKT signaling pathway, supporting that PTPRG plays a tumor suppressive role. 110 In addition, PTPRG cooperates with OPCML to dephosphorylate AXL, mitigating the cell migration and invasion in ovarian cancer. 111 Furthermore, PTPRG was downregulated in patients with chronic myeloid leukemia. 112 It dephosphorylates β-catenin and thus causes it cytosolic degradation, resulting in a repression of cell proliferation, suggesting PTPRG suppresses tumor growth. 113 PTPRG is considered as a predictor of outcome for sarcoma caused by fibroblast growth factor receptors (FGFRs). PTPRG colocalizes with FGFR1 at the plasma membrane, it dephosphorylates and activates FGFR1 in osteosarcoma cells. 114 The lack of PTPRG even attenuates the efficacy of FGFR inhibitors and might serve as a mechanism of FGFR inhibitors resistance. 114 8 | R7 SUBFAMILY R7 subfamily has two members: PTPRR and PTPN5. PTPRR has a single PTP domain in the ICD, and its ECD structure is quite different from other RPTPs. 5 PTPRR is obviously down-regulated in a transcriptome study of 32 colorectal adenomas precancerous tissues. It is reported that a combination therapy of 5-AzaC (a DNA methyltransferase inhibitor) and TSA (histone deacetylase inhibitor) restores the expression of PTPRR successfully, suggesting that CpG island hypermethylation is the reason for PTPRR downregulation. 115 A similar result is also found in cervix squamous carcinomas and cervix adenocarcinomas. 116 PTPRR inhibits ERK1/2 and the expression of AP-1 in MAPK pathway. AP-1 binds to the long control region of HPV to increase the expression of the viral oncoproteins E6/E7, which correlates with CC cell growth. 117 In prostate cancer, PTPRR also plays a role in ERK1/2 dephosphorylation. 118 In ovarian cancer, PTPRR dephosphorylates tyrosine of β-catenin at Tyr-142 by binding α-catenin and it inhibits the activation of the Wnt/β-catenin pathway. 119  Ferroptosis is a form of regulated cell death implicated in cancer context. It is induced by iron-dependent lipid peroxides accumulation that results in oxidative damage. [123][124][125] Besides redox homeostasis factors, ferroptosis is also regulated by various signaling pathways including Wnt/beta-catenin signaling, PI3K-AKT signaling, and JAK-STAT pathway. It is reported that the activation of the Wnt/betacatenin signaling caused ferroptosis resistance by targeting GPX4 in gastric cancer. 126 Activating mutation of PI3K-AKT signaling inhibits ferroptosis via lipogenesis. 127 IFNγ enhances ferroptosis through JAK-STAT pathway in adrenocortical carcinoma and hepatocellular carcinoma. 128,129 In recent years, medicines designed as ferroptosis inducer are becoming new approach for clinical cancer therapy. 130,131 However, tumor cells can increase antioxidant genes to confer F I G U R E 2 Summary of RPTPs in cancer related signaling pathways. The RPTPs regulate multiple signaling pathways including JAK-STAT3, PI3K/AKT, MAPK, Wnt and NF-κB pathways ferroptosis, which may even promote tumor development. 126

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

ETHICS STATEMENT
This study did not involve ethical approval.