Phosphatase Subfamily PTPN13

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN13 (FAP-1/PTP1E/PTPL1/PTP-BAS)

PTPN13 is a non-receptor PTP with diverse functions in intercellular signaling.

Evolution

PTPN13 is found in holozoa, but lost in ecdysozoa (including nematodes and insects). It has a single member in human, PTPN13 (FAP-1/PTP1E/PTPL1/PTP-BAS).

Domain Structure

PTPN13 has FERM domain, followed by five PDZ domains and a PTP phosphatase domain. The earliest form, in Monosiga, has 7 PDZ domains.

FERM domain are usually found in proteins at the interface between the plasma membrane and the cytoskeleton. The FERM domain of PTPN13 can bind to phosphatidyl-inositol-4,5-bisphosphate (PtdIns(4,5)P2) and this binding is important for plasma membrane localization of PTPN13 [1].

The five PDZ domains mediates the interactions between PTPN13 and different proteins in a specific manner:

• PDZ1 mediates the interaction between PTPN13 and:
  • IkappaBalpha (the N-terminal three ankyrin repeats) [2]
  • PLEKHA1/TAPP1 and PLEKHA2/TAPP2. They are localized to the plasma membrane where it specifically binds phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P(2)). The binding maintains PTPN13 in the cytoplasm. Following stimulation of cells with hydrogen peroxide to induce PtdIns(3,4)P(2) production, PTPN13 complexed to TAPP1, translocates to the plasma membrane [3].

• PDZ2 mediates the interactions between PTPN13 and:
  • Fas receptor [4]
  • Tumor suppressor protein APC [5]
  • Zyxin-related protein TRIP6/ZRP-1 [6, 7]
  • small adaptor protein RIL [8]
  • CR1 (complement component (3b/4b) receptor 1 (Knops blood group)) [9]
  • PTEN. PTEN binds to PDZ2/PTPN13 domain in a manner that depends on the specific PTPN13 PDZ domain arrangement involving the interdomain region between PDZ1 and PDZ2 [10].

Two versions of the PDZ2 domain are generated by alternative splicing. The domains differ by the insertion of five amino acid residues and their affinity to the tumour suppressor protein APC [5]. Whereas PDZ2a is able to bind APC in the nanomolar range, PDZ2b shows no apparent interaction with APC [11].

A unique feature of PDZ2 compared to the canonical PDZ fold is an extended flexible loop at the base of the binding pocket [12]. Because of unique feature in sequence and structure, intense studies have been carried upon PDZ2 [13].

• PDZ3 mediates the interaction between PTPN13 and:
  • Fas receptor [14]
  • The extreme C-terminus of PKN2/PRK2 (AGC group, PKN family according to KinBase). A conserved C-terminal cysteine of PRK2 is indispensable for the interaction [15].
  • NGFR/p75(NTR), nerve growth factor receptor. PTPN13 binds to the NGFR cytoplasmic domain in vivo through the interaction between PDZ3 and C-terminal Ser-Pro-Val residues of NGFR [16]. Note: Nerve growth factor receptors consists of two groups: p75 family and Trk family of tyrosine kinases.
  • CR1 (complement component (3b/4b) receptor 1 (Knops blood group)) [9]

• PDZ4 mediates the interaction between PTPN13 and:
  • Fas receptor [17]
  • ARHGAP29/PARG1 (Rho GTPase activating protein (GAP) 29) (the four most C-terminal residues [18]
  • LIM domain-containing adaptor protein CRIP2 [19]

• PDZ5 mediates the interaction between PTPN13 and:
  • CR1 (complement component (3b/4b) receptor 1 (Knops blood group)) [9]

The phosphatase domain crystal structure has been solved [20].

Functions

PTPN13 is widely expressed in normal human tissues and partly overlaps with Fas expression [21, 22, 23]. PTPN13 has several substrates:

• Fas receptor (FasR/TNFRSF6), PTPN13 is also named Fap-1 (Fas-associated phosphatase 1), which negatively regulates Fas but not TRAIL apoptotic signaling through dephosphorylation of FasR. Dephosphorylation FasR by PTPN13 reduces FasR cell surface expression and activity. PTPN13 binds to FasR at the C-terminal 15 amino acids of FasR [24, 25, 26].

• Src kinase. PTPN13 inhibits Src through direct dephosphorylation of Tyr-419 [27].

• Her2/ErbB2. PTPN13 inhibits Her2 activity by dephosphorylating the signal domain of Her2 and plays a role in attenuating invasiveness and metastasis of Her2 overactive tumors [28].

• IRS1 (insulin receptor substrate-1). PTPN13 specifically dephosphorylates IRS1 in vitro and in vivo. IRS1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 (IGF-1) receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways [29].

• Glycogen synthase kinase beta (GSK3beta). PTPN13 interacts with adenomatous polyposis coli (Apc) protein, which participates in a complex that includes GSK3beta and beta-catenin. PTPN13 decreases activity and tyrosine phosphorylation of GSK3beta. GSK3beta phosphorylates beta-catenin and facilitates beta-catenin ubiquitination and degradation by the proteasome [30].

• p85beta, a regulatory subunit of Phosphoinositide 3-kinase (PI3K). PTPN13 dephosphorylates pTyr-655 of p85beta and stimulates p85beta binding to and degradation through F-box protein FBXL2 [31].

• Protein kinase C delta type (PKCdelta), a member of Protein kinase C family which is involved in B cell signaling and in the regulation of growth, apoptosis, and differentiation of a variety of cell types. PTPN23 regulates PKCdelta phosphorylation on Thr505 in prostate cancer cells [32].

• IkappaBalpha (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) is one member of a family of cellular proteins that function to inhibit the NF-kappaB transcription factor, as evidenced from in vitro dephosphorylation reaction and substrate trapping mutant experiments [33].

• ERK and MEK. PTPN13 attenuates MEK and ERK phosphorylation [34], though they are not known to be direct substrates.

• EphrinB1 a ligand of Eph receptor tyrosine kinases. PPTPN13 loss increased phosphorylated EphrinB1 [35], but is not known to be a substrate..

PTPN13 interacts with other proteins with PDZ domains (see Domain section above).

PTPN13 is regulated by:

• STAT3 binding to PTPN13's promoter [36]
• Transcription factor interferon consensus sequence binding protein (Icsbp) in cooperation with Tel and histone deacetylase 3 (Hdac3) repress PTPN13 [37, 38]
• Transcription factor EWS-FLI1 [39]
• miR-200c [40, 41]
• PTPN13 is a substrate of protein kinase A, but little is known about whether protein kinase A regulates PTPN13 [42].

In addition, PTPN13 together with β-catenin regulates the quiescence of hematopoietic stem cells (HSCs) [43].

PTPN13 and cancer

PTPN13 is implicated in cancer. The impact of PTPN13 on cancer is divided between its capacity to counteract the activity of oncogenic tyrosine kinases (as tumor suppressor), its inhibitory interaction with the death receptor, Fas (as oncogene) [44]. Furthermore, PTPN13 has a key role in the apoptotic process in human breast cancer cells independent of Fas but associated with an early inhibition of the insulin receptor substrate-1/phosphatidylinositol 3-kinase pathway [45]. Here are some examples:

PTPN13 has proapoptotic functions and can suppress tumorigenesis. However, its tumor suppressor functions were frequently disrupted epigenetically in multiple lymphomas and carcinomas owing to the methylation of a bidirectional promoter. It is worthy pointing out the promoter is in common with MAPK10/JNK3, which also functions as proapototic gene and tumor suppressor [46].

PTPN13 acts as a putative tumor suppressor gene in hepatocarcinogenesis. It could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation [47].

PTPN13 correlates significantly with Fas resistance in ovarian cancer cell lines and is commonly expressed in ovarian cancers [48].

PTPN13 mediates the activation of NF-kappaB and induces resistance of head and neck cancer to Fas-induced apoptosis [49].

References

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