Phosphatase Subfamily PTPN13
PTPN13 is a non-receptor PTP with diverse functions in intercellular signaling.
PTPN13 is found in holozoa, but lost in ecdysozoa (including nematodes and insects). It has two human members, PTPN13 (FAP-1/PTP1E/PTPL1/PTP-BAS) and PTPN20. PTPN20 emerged in sarcopterygii,which include the coelacanths, lungfish, and the tetrapods. PTPN20 duplicated soon after it's emergence, with both copies losing part of their sequence: One has N-terminal region pseudogenized, which resulted in FRMPD2B (pseudogene) and PTPN20 (protein-coding); another one has C-terminal region pseudogenized, which resulted in FRMPD2 (protein-coding) and PTPN20C (pseudogene).
PTPN13 typically has a FERM domain followed by five PDZ domains and a PTP phosphatase domain. The earliest form, in Monosiga, has 7 PDZ domains.
FERM domains 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 .
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) 
- 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 .
- PDZ2 mediates the interactions between PTPN13 and:
- Fas receptor 
- Tumor suppressor protein APC 
- Zyxin-related protein TRIP6/ZRP-1 [6, 7]
- small adaptor protein RIL 
- CR1 (complement component (3b/4b) receptor 1 (Knops blood group)) 
- 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 .
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 . Whereas PDZ2a is able to bind APC in the nanomolar range, PDZ2b shows no apparent interaction with APC .
A unique feature of PDZ2 compared to the canonical PDZ fold is an extended flexible loop at the base of the binding pocket . Because of unique feature in sequence and structure, intense studies have been carried upon PDZ2 .
- PDZ3 mediates the interaction between PTPN13 and:
- Fas receptor 
- 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 .
- 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 . 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)) 
- PDZ4 mediates the interaction between PTPN13 and:
- Fas receptor 
- ARHGAP29/PARG1 (Rho GTPase activating protein (GAP) 29) (the four most C-terminal residues 
- LIM domain-containing adaptor protein CRIP2 
- PDZ5 mediates the interaction between PTPN13 and:
- CR1 (complement component (3b/4b) receptor 1 (Knops blood group)) 
The phosphatase domain crystal structure has been solved .
PTPN20 has a single phosphatase domain, and a short N-terminal extension.
- 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 .
- 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 .
- 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 .
- 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 .
- 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 .
- 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 .
- 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 .
- ERK and MEK. PTPN13 attenuates MEK and ERK phosphorylation , though they are not known to be direct substrates.
- EphrinB1 a ligand of Eph receptor tyrosine kinases. PPTPN13 loss increased phosphorylated EphrinB1 , 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 
- 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 
- miR-200c [40, 41]
- PTPN13 is a substrate of protein kinase A, but little is known about whether protein kinase A regulates PTPN13 .
In addition, PTPN13 together with β-catenin regulates the quiescence of hematopoietic stem cells (HSCs) .
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) . 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 . 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 .
PTPN13 acts as a putative tumor suppressor gene in hepatocarcinogenesis. It could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation .
PTPN13 correlates significantly with Fas resistance in ovarian cancer cell lines and is commonly expressed in ovarian cancers .
PTPN13 mediates the activation of NF-kappaB and induces resistance of head and neck cancer to Fas-induced apoptosis .
PTP20 is expressed in a wide range of both normal and transformed cell lines . RNA-seq data from GTEx shows it is expressed at very low level. PTPN20 locates to the nucleus and the microtubule network, colocalizing with the microtubule-organizing centre and intracellular membrane compartments, including the endoplasmic reticulum and the Golgi apparatus. Stimulation of cells with epidermal growth factor, osmotic shock, pervanadate, or integrin ligation targeted PTPN20 to actin-rich structures that included membrane ruffles . Human PTPN20 exhibited catalytic activity towards tyrosyl phosphorylated substrates .
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- Maekawa K, Imagawa N, Naito A, Harada S, Yoshie O, and Takagi S. Association of protein-tyrosine phosphatase PTP-BAS with the transcription-factor-inhibitory protein IkappaBalpha through interaction between the PDZ1 domain and ankyrin repeats. Biochem J. 1999 Jan 15;337 ( Pt 2):179-84.
- Kimber WA, Deak M, Prescott AR, and Alessi DR. Interaction of the protein tyrosine phosphatase PTPL1 with the PtdIns(3,4)P2-binding adaptor protein TAPP1. Biochem J. 2003 Dec 1;376(Pt 2):525-35. DOI:10.1042/BJ20031154 |
- Kozlov G, Gehring K, and Ekiel I. Solution structure of the PDZ2 domain from human phosphatase hPTP1E and its interactions with C-terminal peptides from the Fas receptor. Biochemistry. 2000 Mar 14;39(10):2572-80.
- Erdmann KS, Kuhlmann J, Lessmann V, Herrmann L, Eulenburg V, Müller O, and Heumann R. The Adenomatous Polyposis Coli-protein (APC) interacts with the protein tyrosine phosphatase PTP-BL via an alternatively spliced PDZ domain. Oncogene. 2000 Aug 10;19(34):3894-901. DOI:10.1038/sj.onc.1203725 |
- Murthy KK, Clark K, Fortin Y, Shen SH, and Banville D. ZRP-1, a zyxin-related protein, interacts with the second PDZ domain of the cytosolic protein tyrosine phosphatase hPTP1E. J Biol Chem. 1999 Jul 16;274(29):20679-87.
- Cuppen E, van Ham M, Wansink DG, de Leeuw A, Wieringa B, and Hendriks W. The zyxin-related protein TRIP6 interacts with PDZ motifs in the adaptor protein RIL and the protein tyrosine phosphatase PTP-BL. Eur J Cell Biol. 2000 Apr;79(4):283-93. DOI:10.1078/S0171-9335(04)70031-X |
- van den Berk LC, van Ham MA, te Lindert MM, Walma T, Aelen J, Vuister GW, and Hendriks WJ. The interaction of PTP-BL PDZ domains with RIL: an enigmatic role for the RIL LIM domain. Mol Biol Rep. 2004 Dec;31(4):203-15.
- Ghiran I, Glodek AM, Weaver G, Klickstein LB, and Nicholson-Weller A. Ligation of erythrocyte CR1 induces its clustering in complex with scaffolding protein FAP-1. Blood. 2008 Oct 15;112(8):3465-73. DOI:10.1182/blood-2008-04-151845 |
- Sotelo NS, Schepens JT, Valiente M, Hendriks WJ, and Pulido R. PTEN-PDZ domain interactions: binding of PTEN to PDZ domains of PTPN13. Methods. 2015 May;77-78:147-56. DOI:10.1016/j.ymeth.2014.10.017 |
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- Kozlov G, Banville D, Gehring K, and Ekiel I. Solution structure of the PDZ2 domain from cytosolic human phosphatase hPTP1E complexed with a peptide reveals contribution of the beta2-beta3 loop to PDZ domain-ligand interactions. J Mol Biol. 2002 Jul 19;320(4):813-20.
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- Gross C, Heumann R, and Erdmann KS. The protein kinase C-related kinase PRK2 interacts with the protein tyrosine phosphatase PTP-BL via a novel PDZ domain binding motif. FEBS Lett. 2001 May 11;496(2-3):101-4.
- Irie S, Hachiya T, Rabizadeh S, Maruyama W, Mukai J, Li Y, Reed JC, Bredesen DE, and Sato TA. Functional interaction of Fas-associated phosphatase-1 (FAP-1) with p75(NTR) and their effect on NF-kappaB activation. FEBS Lett. 1999 Oct 29;460(2):191-8.
- Saras J, Engström U, Góñez LJ, and Heldin CH. Characterization of the interactions between PDZ domains of the protein-tyrosine phosphatase PTPL1 and the carboxyl-terminal tail of Fas. J Biol Chem. 1997 Aug 22;272(34):20979-81.
- Saras J, Franzén P, Aspenström P, Hellman U, Gonez LJ, and Heldin CH. A novel GTPase-activating protein for Rho interacts with a PDZ domain of the protein-tyrosine phosphatase PTPL1. J Biol Chem. 1997 Sep 26;272(39):24333-8.
- van Ham M, Croes H, Schepens J, Fransen J, Wieringa B, and Hendriks W. Cloning and characterization of mCRIP2, a mouse LIM-only protein that interacts with PDZ domain IV of PTP-BL. Genes Cells. 2003 Jul;8(7):631-44.
- Villa F, Deak M, Bloomberg GB, Alessi DR, and van Aalten DM. Crystal structure of the PTPL1/FAP-1 human tyrosine phosphatase mutated in colorectal cancer: evidence for a second phosphotyrosine substrate recognition pocket. J Biol Chem. 2005 Mar 4;280(9):8180-7. DOI:10.1074/jbc.M412211200 |
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- Glondu-Lassis M, Dromard M, Lacroix-Triki M, Nirdé P, Puech C, Knani D, Chalbos D, and Freiss G. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res. 2010 Jun 15;70(12):5116-26. DOI:10.1158/0008-5472.CAN-09-4368 |
- Zhu JH, Chen R, Yi W, Cantin GT, Fearns C, Yang Y, Yates JR 3rd, and Lee JD. Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene. 2008 Apr 17;27(18):2525-31. DOI:10.1038/sj.onc.1210922 |
- Dromard M, Bompard G, Glondu-Lassis M, Puech C, Chalbos D, and Freiss G. The putative tumor suppressor gene PTPN13/PTPL1 induces apoptosis through insulin receptor substrate-1 dephosphorylation. Cancer Res. 2007 Jul 15;67(14):6806-13. DOI:10.1158/0008-5472.CAN-07-0513 |
- Huang W, Bei L, and Eklund EA. Fas-associated phosphatase 1 (Fap1) influences βcatenin activity in myeloid progenitor cells expressing the Bcr-abl oncogene. J Biol Chem. 2013 May 3;288(18):12766-76. DOI:10.1074/jbc.M112.429696 |
- Kuchay S, Duan S, Schenkein E, Peschiaroli A, Saraf A, Florens L, Washburn MP, and Pagano M. FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade. Nat Cell Biol. 2013 May;15(5):472-80. DOI:10.1038/ncb2731 |
- Castilla C, Chinchón D, Medina R, Torrubia FJ, Japón MA, and Sáez C. PTPL1 and PKCδ contribute to proapoptotic signalling in prostate cancer cells. Cell Death Dis. 2013 Apr 4;4:e576. DOI:10.1038/cddis.2013.90 |
- Nakai Y, Irie S, and Sato TA. Identification of IkappaBalpha as a substrate of Fas-associated phosphatase-1. Eur J Biochem. 2000 Dec;267(24):7170-5.
- Hoover AC, Strand GL, Nowicki PN, Anderson ME, Vermeer PD, Klingelhutz AJ, Bossler AD, Pottala JV, Hendriks WJ, and Lee JH. Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway. Oncogene. 2009 Nov 12;28(45):3960-70. DOI:10.1038/onc.2009.251 |
- Vermeer PD, Bell M, Lee K, Vermeer DW, Wieking BG, Bilal E, Bhanot G, Drapkin RI, Ganesan S, Klingelhutz AJ, Hendriks WJ, and Lee JH. ErbB2, EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling in human cancers. PLoS One. 2012;7(1):e30447. DOI:10.1371/journal.pone.0030447 |
- Han XJ, Xue L, Gong L, Zhu SJ, Yao L, Wang SM, Lan M, Zhang W, and Li YH. Stat3 inhibits PTPN13 expression in squamous cell lung carcinoma through recruitment of HDAC5. Biomed Res Int. 2013;2013:468963. DOI:10.1155/2013/468963 |
- Huang W, Zhu C, Wang H, Horvath E, and Eklund EA. The interferon consensus sequence-binding protein (ICSBP/IRF8) represses PTPN13 gene transcription in differentiating myeloid cells. J Biol Chem. 2008 Mar 21;283(12):7921-35. DOI:10.1074/jbc.M706710200 |
- Huang W, Hu L, Bei L, Hjort E, and Eklund EA. The leukemia-associated fusion protein Tel-platelet-derived growth factor receptor β (Tel-PdgfRβ) inhibits transcriptional repression of PTPN13 gene by interferon consensus sequence binding protein (Icsbp). J Biol Chem. 2012 Mar 9;287(11):8110-25. DOI:10.1074/jbc.M111.294884 |
- Abaan OD, Levenson A, Khan O, Furth PA, Uren A, and Toretsky JA. PTPL1 is a direct transcriptional target of EWS-FLI1 and modulates Ewing's Sarcoma tumorigenesis. Oncogene. 2005 Apr 14;24(16):2715-22. DOI:10.1038/sj.onc.1208247 |
- Schickel R, Park SM, Murmann AE, and Peter ME. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 2010 Jun 25;38(6):908-15. DOI:10.1016/j.molcel.2010.05.018 |
- Ramachandran S, Ilias Basha H, Sarma NJ, Lin Y, Crippin JS, Chapman WC, and Mohanakumar T. Hepatitis C virus induced miR200c down modulates FAP-1, a negative regulator of Src signaling and promotes hepatic fibrosis. PLoS One. 2013;8(8):e70744. DOI:10.1371/journal.pone.0070744 |
- Nedachi T and Conti M. Potential role of protein tyrosine phosphatase nonreceptor type 13 in the control of oocyte meiotic maturation. Development. 2004 Oct;131(20):4987-98. DOI:10.1242/dev.01368 |
- López-Ruano G, Prieto-Bermejo R, Ramos TL, San-Segundo L, Sánchez-Abarca LI, Sánchez-Guijo F, Pérez-Simón JA, Sánchez-Yagüe J, Llanillo M, and Hernández-Hernández Á. PTPN13 and β-Catenin Regulate the Quiescence of Hematopoietic Stem Cells and Their Interaction with the Bone Marrow Niche. Stem Cell Reports. 2015 Oct 13;5(4):516-31. DOI:10.1016/j.stemcr.2015.08.003 |
- Freiss G and Chalbos D. PTPN13/PTPL1: an important regulator of tumor aggressiveness. Anticancer Agents Med Chem. 2011 Jan;11(1):78-88.
- Bompard G, Puech C, Prébois C, Vignon F, and Freiss G. Protein-tyrosine phosphatase PTPL1/FAP-1 triggers apoptosis in human breast cancer cells. J Biol Chem. 2002 Dec 6;277(49):47861-9. DOI:10.1074/jbc.M208950200 |
- Ying J, Li H, Cui Y, Wong AH, Langford C, and Tao Q. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia. 2006 Jun;20(6):1173-5. DOI:10.1038/sj.leu.2404193 |
- Yeh SH, Wu DC, Tsai CY, Kuo TJ, Yu WC, Chang YS, Chen CL, Chang CF, Chen DS, and Chen PJ. Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res. 2006 Feb 15;12(4):1097-108. DOI:10.1158/1078-0432.CCR-05-1383 |
- Meinhold-Heerlein I, Stenner-Liewen F, Liewen H, Kitada S, Krajewska M, Krajewski S, Zapata JM, Monks A, Scudiero DA, Bauknecht T, and Reed JC. Expression and potential role of Fas-associated phosphatase-1 in ovarian cancer. Am J Pathol. 2001 Apr;158(4):1335-44. DOI:10.1016/S0002-9440(10)64084-9 |
- Wieckowski E, Atarashi Y, Stanson J, Sato TA, and Whiteside TL. FAP-1-mediated activation of NF-kappaB induces resistance of head and neck cancer to Fas-induced apoptosis. J Cell Biochem. 2007 Jan 1;100(1):16-28. DOI:10.1002/jcb.20922 |
- Fodero-Tavoletti MT, Hardy MP, Cornell B, Katsis F, Sadek CM, Mitchell CA, Kemp BE, and Tiganis T. Protein tyrosine phosphatase hPTPN20a is targeted to sites of actin polymerization. Biochem J. 2005 Jul 15;389(Pt 2):343-54. DOI:10.1042/BJ20041932 |