Important roles of Protein Tyrosine Phosphatase PTPN12 in Tumor Progression

Authors: Chaelin Lee, Inmoo Rhee

PII: S1043-6618(19)30495-5
Reference: YPHRS 4227

To appear in: Pharmacological Research

Received date: 20 March 2019
Revised date: 26 March 2019
Accepted date: 4 April 2019

Please cite this article as: Lee C, Rhee I, Important roles of Protein Tyrosine Phosphatase PTPN12 in Tumor Progression, Pharmacological Research (2019),

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for Pharmacological Research

Important roles of Protein Tyrosine Phosphatase PTPN12 in Tumor

Chaelin Lee1 and Inmoo Rhee1,*

Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea

*Correspondence: Inmoo Rhee, Sejong University, 209 Neungdongro, Gwangjingu, Seoul, KOREA 05006
e-mail: [email protected] phone: +82-2-6935-2432 FAX: +82-2-3408-3443

Graphical abstract

Chemical compounds studied in this article: dephostatin (PubChem CID: 2990), sodium stibogluconate (PubChem CID: 16683013), phenylarsine oxide (PubChem CID: 131726110), vanadate (PubChem CID: 61672), gallium nitrate (PubChem CID: 61635), suramin (PubChem CID: 5361), aplidin (PubChem CID: 9812534), MSI-1436 (PubChem CID: 9917968), SHP099 (PubChem CID: 118238298), RMC-4550 (PubChem CID: 134183206)


Protein tyrosine phosphatases (PTPs), which are ubiquitously expressed in hematopoietic and non- hematopoietic cells, are critical for regulating cell proliferation as well as differentiation in the physiology of multicellular organisms. PTPs regulate the intracellular signaling mechanism of immune cells via dephosphorylation of multiple targets and are associated with the onset of various autoimmune diseases through genomic alterations. PTPs also affect disease through their role in innate and/or acquired immunity. By modulating multiple substrates, PTPN12, a member of the proline-, glutamic acid-, serine- and threonine-rich (PEST) family of PTPs, is an important regulator of cell migration and adhesion. According to its newly identified roles and functions, PTPN12 is considered a promising therapeutic target against critical diseases, including cancer, diabetes, metabolic disease and autoimmune diseases. In this review, we provide an overview of PTPs and discuss the critical roles of PTPN12/PTP-PEST in tumor progression.


CD2BP1 CD2 binding protein1
CDK2 Cyclin-dependent kinase 2
CID Chemistry in disks
FOXO Forkhead box
IKK IκB kinase 
LFA-1 Lymphocyte function-associated antigen 1
LIM Lin11, Isl-1 & Mec-3
NPLH asparagine, proline, leucine and histidine
PAK1 Serine/Threonine-protein kinase 1
PEST Proline-, Glutamate-, Serine-, Threonine-
PSTPIP Proline-serine-threonine phosphatase-interacting protein
PTK Protein Tyrosine Kinase
PTP Protein Tyrosine Phosphatase
PTPN12 Protein Tyrosine Phosphatase 12
PYCARD PYD And CARD Domain Containing
SFK Src Family Kinase
SH3 SRC Homology 3
SHP-1 Src homology region 2 domain-containing phosphatase-1
TCR T cell Receptor
TNBC Triple Negative Breast Cell
WPD tryptophan, proline and aspartate

Keywords: Protein tyrosine phosphatases; PTPN12/PTP-PEST; Phosphorylation; Breast cancer; Signal transduction; Inhibitors


Protein phosphorylation is one of the most prevalent post-translational modifications [1]. It is a prominent signal transduction and cellular regulatory mechanism, with involvement in mediating all basic cellular processes including regulation of protein interactions, gene transcription, cellular growth/proliferation/differentiation/transformation, immune response and metabolism [2].

Phosphorylation is a reversible, covalent protein modification that principally occurs at the hydroxyl group on the side chain of three amino acids: serine, threonine, and tyrosine [2,3]. Protein phosphorylation is a dynamic process in which a phosphate group is added by kinases and removed by phosphatases [3]. The importance of serine/threonine/tyrosine kinases and phosphatases in cell physiology has been extensively studied in organisms ranging from bacteria to humans as well as viruses, and this modification has been shown to play a key role in regulatory processes [4,5]. Phosphorylation on tyrosine, mediated by protein tyrosine kinases (PTKs), is a post-translational modification that can be rapidly reversed by protein tyrosine phosphatases (PTPs) [5-7]. Moreover, PTKs and PTPs are highly regulated to maintain a dynamic balance between the phosphorylated and dephosphorylated state of a signaling molecule and maintaining the equilibrium between PTKs and PTPs is critical for the maintenance of immune systems [5]. Importantly, disruption of this equilibrium results in a plethora of human diseases involving immunodeficiency, autoimmunity or malignancy [8- 10].


As mentioned above, PTPs are major regulators of PTKs via dephosphorylation of phosphorylated tyrosine residues on proteins [3,11-13] and are critical for signal transduction pathways as well as controlling various cellular functions indicating protein interaction/stability, cellular motility, and enzyme activity [7,9,11,14,15]. A total of 125 PTP genes, including 81 encoding ‘active’ PTPs, have been identified in the human genome (Table 1) [2,12,16]. Of these, only 38 members, the so-called classical PTPs, are tyrosine specific [12,17]. Dual-specific PTPs, the members of which also catalyze dephosphorylation of serine/threonine, and even RNA, comprise a large group of 63 proteins [18]. Tyrosine specific PTPs can be subdivided into receptor-type PTPs and non-receptor-type PTPs according to their unique structural and functional properties [14].


The PEST family PTPs are non-receptor type phosphatases consisting of proline-enriched phosphatase (PEP) in mice and lymphoid tyrosine phosphatase (LYP) in humans (also named PTPN22 and PTPN8), PTP-PEST (PTPN12), and PTP-hematopoietic stem cell fraction (PTP-HSCF; PTPN18) (Figure 1) [19-21]. PEP/LYP is expressed exclusively in immune cells, whereas PTPN12 is expressed in both non-hematopoietic and hematopoietic cells [19,22]. In contrast, PTP-HSCF expression is restricted to primitive hematopoietic cells [23]. These PTPs share common structural features including an N-terminal phosphatase domain, proline-rich sequences and a tyrosine phosphorylation site as well as a carboxyl-terminal homology (CTH) domain. PEST family PTPs are phosphorylated on serine (Ser) residues: Ser35 for PTPN22, Ser39 for PTPN12 and Ser37 for PTPN18. These PTPs also have a quite unique domain, conserved CTH domain at the end. It has been shown to bind to adapter proteins, such as PSTPIP1 and PSTPIP2 with PTP-PEST and PTP-HSCF, respectively but the binding substrates for PEP/Lyp have not been determined yet.

PTPN12 (PTP-PEST) Discovery of PTPN12
PTPN12, also known as PTP-PEST, was first discovered in 1992 as an 88 kDa cytosolic PTP that is ubiquitously expressed in mammalian tissues [24,25]. PTPN12 was also subsequently characterized in mouse cells as a cytosolic PTP of 120 kDa (~775 amino acids) that is phosphorylated on serine and threonine residues and is rich in proline (P), glutamate (E), serine (S), and threonine (T) residues [24,26].

Structure and Expression of PTPN12

PTPN12 is highly and broadly expressed in both hematopoietic cells and non-hematopoietic cells, and it accumulates in high amounts in cells of hematopoietic tissues such as thymus, spleen and liver. The murine PTPN12 gene consists of 18 exons and spans more than 90 kb region of the genome. The phosphatase domain of PTPN12 is encoded by 10 exons, from exon 2 to 11 [19]. The human PTPN12 gene has been mapped to chromosome 7q11.23 and the corresponding gene in mice has been localized to the centromeric portion of chromosome 5. PTPN12 contains a 50 ~ 60 amino acid N-terminal region followed by a 240 amino acid PTP catalytic domain (catalytic residues Cys231 and Arg237) that mediates phosphatase activity [19,20]. PTPN12 also contains a C-terminal tail of approximately 500 amino acids that contains PEST sequences and four proline-rich domains (P1, P2, P3, P4) as well as an NPLH sequence harboring signal transduction motifs (Figure 1) [19,20]. The phosphatase activity of PTPN12 towards phosphorylated tyrosine is regulated by a specific phosphorylation site at Ser39, which has been critically identified as a major inhibitory phosphorylation site for PTPN12 [4,27].

Protein Interactions and Functions of PTPN12

Ubiquitously expressed PTPN12 is found mainly in the cytoplasm and is involved in regulating cell migration, focal adhesions, and antigen receptor signal transduction in immune cells. PTPN12

exerts these various regulatory functions through interactions with cellular proteins via four proline- rich motifs (P1-P4) and unique domains in non-catalytic carboxyl residues. PTPN12 binds to the adaptor protein Crk-associated substrate (Cas), and its relatives Sin and CasL, via the P1. PTPN12 also interacts with the LIM domains of paxillin (and its relatives Hic-5 and leupaxin) as well as protein tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK) through the P2 [28,29]. PTPN12 associates with the both the SH3 domains of the Grb2 through its P1, P3, P4, CTH and with the inhibitory PTK, C-terminal Src kinase (Csk) via the P4 [30,31]. In addition to its proline-rich domains, PTPN12 contains an NPLH sequence, which promotes association with the phosphotyrosine binding (PTB) domain of Shc [32]. Moreover, the CTH domain of PTPN12 binds two other scaffold proteins via the coiled-coil domain from the murine protein PSTPIP1 (human counterpart, CD2BP1) and PSTPIP2, and both of these scaffold proteins are involved in cytoskeletal regulation [21,33]. PTPN12 has a central -sheet flanked by -helices, providing key active sites. A specific linker connects two - helices of the sequence MKSPDHNG to recognize the cyclin-dependent protein kinases. PTPN12 also has unique domains different from other PEST family members including the WPD-loop, 1-4 loops and 1’ helix, which enable distinct electrostatic potentials that comprise a continuous, basic, charged groove as well as acidic patches in active sites [34].

PTPN12 in Immune Cells and Non-immune Cells

a.Roles of PTPN12 in fibroblasts and transformed cell lines

Since PTPN12 deficiency causes early embryonic lethality in mice, much of what we know about PTPN12 has been learned from studies of its overexpression or deficiency in fibroblasts and Ptpn12- transformed cell lines instead of knockout mouse model [35,36]. The initially established roles of PTPN12 using cell lines involve modulation of cell migration via regulation of the actin cytoskeletal rearrangement and cell adhesion [36]. Knockdown studies using Ptpn12-deficient cell lines have implicated PTPN12 in cell spreading and focal adhesion disassembly, suggesting its involvement in

multiple steps in the cell migration process [26]. Overexpression of PTPN12 leads to dephosphorylation of Cas and interruption of its communication with Crk [19]. In contrast, Cas is hyperphosphorylated in Ptpn12-deficient cells and its association with Crk is enhanced resulting in a failure of migration [37]. In addition to Cas, PTPN12 interacts with the inhibitory PTK, Csk, and the adaptor proteins Shc and Grb2 [19]. Through the interactions with its substrates, PTPN12 likely exerts its effects on motility via multiple pathways. PTPN12 is also required for the dissociation of focal adhesions by activating integrins. These latter effects are correlated with dephosphorylation of the focal adhesion protein paxillin, Pyk2, c-abl, and PSTPIP, Wiskott-Aldrich syndrome protein (WASP)- binding protein, Vav, and p190Rho-GAP [20,21,28,38,39]. PTPN12 activity is stimulated by cell adhesion, which promotes PTPN12 localization to the edges of membrane protrusions [39]. PTPN12 also regulates events at the leading edge of migrating cells such as membrane ruffling and protrusion through catalytic activity-dependent regulation of the small GTPase Rac1 [40] and positively controls of T and B cell activation, cytoskeletal reorganization, adhesion and migration [20,36].
PTPN12 plays important roles in immune responses (Figure 2). It negatively regulates antigen- mediated activation in T cells and B cells. In T cells, PTPN12 inhibits actin reorganization and immunological synapse formation through the dephosphorylation of WASP and Arp2/3 associated signaling proteins in PTPN12 overexpressed-ovalbumin (OVA)-specific CD4+ T cells from OT-II TCR transgenic mice [29,41]. PTPN12 also downregulates TCR-mediated activation of CD4+ and CD8+ T cells in primary human T cells and the Jurkat cells causing reduced interleukin-2 (IL-2) production and inhibition of nuclear factor of activated T cells (NFATs), nuclear factor kappa B (NF-B) [29]. Moreover, down-regulation of PTPN12 contributes to the enhanced responsiveness of secondarily activated T cells such as effector/memory T cells [29]. Conversely, overexpression of PTPN12 in B cell line A20 results in significant blockade of B cell receptor (BCR)-mediated IL-2 production [20]. PTPN12 in A20 cells dephosphorylates Shc, FAK, Pyk2, and Cas suggesting inhibitory effects [20].

b.Roles of PTPN12 in conditional knockout mouse model

Homozygous deletion of the Ptpn12 gene in mice is embryonically lethal, whereby a constitutive Ptpn12-deficient mouse exhibited embryonic lethality between days 9.5 and 10.5 (E9.5-10.5) with impaired vascular development, absence of liver organogenesis and neuroepithelium degeneration [42]. To bypass this embryonic lethality and address the physiological roles of PTPN12, conditionally targeted mice on the Ptpn12 allele encoding PTPN12 were generated. In primary T cells from these conditionally induced Ptpn12-deficient mice, PTPN12 was shown to be required for secondary T cell activation, anergy regulation, and generation of autoimmunity but was not necessary for primary T cell responses and development [29]. PTPN12 selectively dephosphorylates Pyk2, a substrate of Fyn, and boosts the formation of homoaggregates between T cells mediating via integrin such as LFA-1 [29]. PTPN12 is also important for regulating dendritic cell migration and T cell dependent autoimmunity in dendritic cells by dephosphorylating substrates such as Pyk2 and paxillin [43]. Furthermore, PTPN12 positively regulates activation of T and B cells, cytoskeletal reorganization, adhesion and migration [20,36]. PTPN12 is potentially a negative regulator of auto-inflammatory disorders including pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis (FRA) due to alteration of its substrate, PSTPIP1 [44]. PTPN12 associates with CD2 and decreases CD2-stimulated cellular adhesion. Additionally, it is critical in innate immunity and the inflammatory response by recruiting to inflammasomes via the familial Mediterranean fever gene (MEFV) gene (also named as pyrin). PTPN12 is associated with MEFV, which binds with PYCARD, the main component of the inflammasome, and induces the formation of pyroptosomes causing inflammatory apoptosis by the formation of large complexes [45].
In addition, PTPN12 is critical for vascular development and embryonic viability in endothelial cells [46]. In primary endothelial cells separated from an inducible Ptpn12-deficient mouse model, PTPN12 was found to be critical for endothelial cell migration and adhesion by dephosphorylating its

substrates, Cas, paxillin, and Pyk2 [46]. Moreover, using this same mouse model, PTPN12 was shown to play an essential role in the fusion of macrophages to form osteoclasts and multinucleated giant cells (MGCs) among primary macrophages from an inducible Ptpn12-deficient mouse [47]. PTPN12 has an essential role in actin rearrangement, migration and adhesion of macrophages during the formation of MGCs [47]. PTPN12 mediates dephosphorylation of the kinase Pyk2 and the adaptor paxillin in this process [47]. Furthermore, PTPN12 has also been linked to the regulation of receptor-mediated apoptosis [48]. It undergoes proteolytic cleavage by caspase-3 causing disruption of protein-protein interactions with its substrates and promoting cellular detachment during apoptosis [48]. PTPN12 also negatively regulates Toll-like receptor (TLR)-triggered innate immune responses by impairing IKKβ/NF-κB activation in macrophages [49]. In addition, it regulates osteoclast differentiation and adhesion to the bone matrix. PTPN12 is found at the sites of podosome structures and the peripheral sealing zone to enhance resorption of osteoclasts via the dephosphorylation of substrates such as leupaxin, gelsolin, WASP, c-Src, Pyk2, and PSTPIP [50-53]. Consistent with this, Ptpn12-deficient osteoclasts were found to exhibit defects in the formation of podosomal structures and bone resorption. PTPN12 is also critical to enhance the differentiation of osteoblasts by the decreased GTPase dynamin [54].

PTPN12 in Tumor Progression

PTPN12 is a tumor suppressor that has been shown to potentiate the inhibition of tumor cell proliferation, tumorigenesis, and metastasis. According to recent reports, PTPN12 exerts significant tumor suppressive effects in triple-negative breast cancer (TNBC) cells and is often inactivated in breast cancer [55,56]. TNBC is generally recognized and distinguished from other breast cancers by its severely malignant symptoms and the absence of three important receptors including the estrogen receptor (ER), progesterone receptor (PR) and human epithermal growth factor receptor tyrosine kinase (HER-2). PTPN12 suppresses the malignant transformation of multiple tyrosine kinases

including epithelial growth factor receptor (EGFR), HER2 and platelet-derived growth factor receptor- beta (PDGFR) in human mammary epithelial cells (HMECs). The recurrent mutations affecting the H230 residue of PTPN12 were observed in patients with TNBC and other tumor types, and the H230Y mutation impairs phosphatase activity, resulting in increased phosphorylation of MET and PDGFR, and reliving the suppression of TNBC cell growth [56]. Overall, PTPN12 inhibits and limits the signaling mechanism via these receptors as a feedback mechanism of tumor suppression [55]. For example, a mutant form of PTPN12 or a reduced level of PTPN12 causes a loss of its regulatory mechanism leading to aberrant activity. However, the normal signaling by PDGFRβ and MET, and the impaired TNBC survival are possibly recovered by restoring PTPN12 protein levels [55]. Additionally, the expression of PTPN12 is important to regulate the methylation of promoter CpG islands in breast cancer cell lines as well as in breast cancer patients.
Moreover, PTPN12 dephosphorylates Pyk2, Cas and paxillin and ultimately performs its critical roles as a tumor suppressor by suppressing multiple cellular mechanisms including cell survival, migration, invasiveness, and the epithelial-to-mesenchymal transition (EMT) [57]. Importantly, CDK2 interacts and phosphorylates PTPN12 at the Ser19 site. Then, anti-tumorigenic roles of PTPN12 are decreased and impaired the localization of PAK1 (Ser/Thr-protein kinase 1) with HER2 to block the HER2-mediated signaling pathway and promote highly increased tumor cell motility [34,58]. Moreover, in papillary renal cell carcinoma (PRCC), reactive oxygen species (ROS)-induced oxidation inactivates PTPN12, decreasing dephosphorylation of ABL1 and resulting in increased tumor growth and survival [59]. PTPN12 also regulates ATP-dependent ubiquitin segregase (p97/Vcp) by mediating phosphorylation of Cas, thereby balancing tumor cell growth and invasion [60]. Interestingly, the microRNA, miR-194 enhances ovarian cancer development and tumor metastasis by negatively regulating PTPN12, and is thus a potential target of drug-development efforts to restore PTPN12 activity [61]. It has also been suggested that PTPN12 regulates the polarization of macrophages indicating negative control of tumor progression [62]. Finally, the common variant T537A, caused by

a single nucleotide polymorphism (SNP), results in a partial loss-of-function in breast cancer patients [63].
Paradoxically, Ptpn12-deficient murine embryonic fibroblasts (MEFs) exhibit high rates of ROS- induced apoptosis under conditions of antioxidant depletion as well as defective activation of the transcription factor FOXO1/3a mediated by phosphoinositide-dependent kinase-1 (PDK1) [64]. The regulation of ROS is correlated with the survival of breast cancer cells and mammary epithelial tumor cells, and the lack of PTPN12 is believed to reduce tumorigenic and metastatic potential activity in TNBC patients with low levels of PTPN12 in TNBC.


As stated above, PTPs are key regulators in the cellular signaling pathways and are involved in various human diseases. After the first discovery of the PTP inhibitor, dephostatin, in the early 1990s, there was increased interest in developing new PTP inhibitors as novel therapeutic drugs becomes widely expanded. Dephostatin was purified from a Streptomyces strain culture and then synthesized from 2-nitrohydroquinone [65]. Dozens of newly discovered PTP inhibitors are being reported including natural products, peptides, phosphonates, mimotopes, and even silencing RNAs [66,67]. Promising natural inhibitors target classical PTPs such as PTP1B, CD45, CDC25, SHP-1 and SHP-2 [66]. However, it is difficult to develop a PTP inhibitor that shows the effective selectivity and bioavailability perfectly targeting both the active site and unique peripheral binding pockets [66]. There are two major concerns indicating that PTPs possess highly conserved active sites for phospho- tyrosine binding sites to confer the selectivity of inhibitors, and there are positively charged active sites, which are supposed to bind with negatively charged drugs that lack cell permeability. Despite several drugs that act as inhibitors of PTP activity (sodium stibogluconate, phenylarsine oxide, vanadate, gallium nitrate, suramin, or aplidin), but the clinically approved specific PTP inhibitors have not been launched yet [68].

Designing drug-like inhibitors for PTPs is challenging due to their highly conserved and positively charged active site structures. However, recent reports from both academia and industry have shown that the covalent and/or allosteric inhibition strategy is an alternative approach to overcoming this problem. In fact, the role of PTP1B in the regulation of insulin and leptin receptor is unclear due to its dual activities in vivo, though it was a chance to accelerate the development of PTP inhibitors by both academia and industry [69,70]. Recently, MSI-1436 as an allosteric inhibitor of PTP1B that was developed as a therapeutic target for diabetes and obesity, was found to positively regulate HER2 signaling in breast cancer development; however, these results are controversial [71]. For instance, PTP1B, which is a critical inhibitor of insulin and the leptin signaling pathway, and the SNP mutant variants of PTPs such as PTPN22 are promising targets for development of new inhibitors [72,73]. SHP099 was developed to target the oncogenic tyrosine phosphate SHP-2, with a highly potent and selective efficiency (IC50 = 71 nM) by suppressing the RAS–ERK signaling in human cancer cells and mouse tumor xenograft models [74]. Moreover, an inhibitor more potent and selective inhibitors than SHP099, RMC-4550 (IC50 =1.5 nM) was developed for the treatment of EGFR-driven esophageal cancer. Although it is difficult to develop specific PTP inhibitor that directly targets its active site, according to a recent study, a nonconserved cysteine residue (C333) targeted selective inhibitor was identified by characterizing its covalently inhibitory activity [75,76].
Aberrant regulation of PTP activity has been connected to various human diseases such as diabetes, obesity, cancer and autoimmune diseases. Therefore, it is expected that the PTP family off ers a critical foundation of molecular targets for novel therapeutic medicines.


Recent accumulating evidence has revealed genetically mutated forms of PTPs in a wide range of human cancers and that PTPs are critically involved in tumorigenesis. A broad range of mutated PTP family genes have been found in a majority of human cancers. Although PTPs are attractive candidates for new anti-tumorigenic immunotherapeutic agents, the development of selective PTP inhibitors remains challenging owing to the highly conserved active site of between tumor suppressor and aberrant PTP subtypes. However, such the limitation of development of PTP inhibitors could be overcome by targeting externally PTP activation sites. Given its important roles as a key regulator controlling immune cells and tumor progression in various types of cancer as well as in human inflammatory and autoimmune diseases, PTPN12 is a promising therapeutic candidate that is available for the treatment of numerous diseases including life-threatening cancers.

Author Contributions: I.R. wrote the manuscript. C.L. helped in writing and formatting the manuscript.

Funding: This research was supported by Research Program To Solve Social Issues of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (No. NRF- 2017M3C8A6091777) and by Basic Science Research program through NRF funded by the Ministry of Education (No. NRF-2019R1H1A2039755).

Conflicts of Interest: The authors declare no conflict of interest.


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Table 1. Protein Tyrosine Phosphatases (PTPs)

Protein tyrosine p Class I Cysteine- based PTPs hosphatases Examples

Receptor-type Classical PTPs PTPs (21) (38)
PTPN12, PTPN22 (LYP/PEP), P T P N 1 8 ( PTP- HSCF), SHP-1, SHP-2, PTP1B

Dual specificity PTPs (61)
MKPs (11)

Atypical DSPs (19)

PRLs (3)

CDC14s (4)MAN PTENs (5)

Slingshots (3)

Myotubularins (16)





Class II Cysteine- based PTPs

Class III Cysteine- based PTPs
Aspartate-based PTPs


EyA (4)



EyA1, EyA2, EyA3, EyA4


Figure 1. The structure of PEST family PTPs. PEST family PTPs consist of catalytic domains including serine phosphorylation site and CTH domains. PTPN12 and PTPN22 possess proline-rich domains (P) that interact with multiple substrates and represent their unique functions. PTPN12 has a unique site, the NPLH sequence introducing Shc, and PTPN22 signifies single nucleotide polymorphism site, R620W.


Figure 2. The multiple functions of PTPN12. PTPN12 is ubiquitously expressed and critically regulates a number of physiological functions in various cell types.