Difference between revisions of "Phosphatase Subfamily PTPN12"

Revision as of 17:16, 13 March 2015

Phosphatase Classification: Fold CC1:Superfamily CC1: Family PTP: Subfamily PTPN12 (PTP-PEST)

Evolution

Domain

Phosphatase domain has crystal structure solved [1].

The noncatalytic domain of PTPN22/LYP contains four proline-rich potential SH3 domain binding sites and an NXXY motif that, if phosphorylated, may be recognized by phosphotyrosine binding (PTB) domains [2].

The region of 301-320 in PTPN22 interactions with its phosphatase domain and reduces its catalytic activity [3].

Functions

PTPN12 (PTP-PEST/PTPG1)

PTPN12 is widely expressed in different tissues and at relatively low level in brain according to GTEx. The expression pattern is consistent with earlier studies [4, 5, 6].

PTPN12 have below substrates and/or interacting partners:

• p130Cas/BCAR1 [7]. p130Cas/BCAR1 is an adaptor protein that regulates multiple signaling pathways leading to cell adhesion, migration, invasion, apoptosis, hypoxia and mechanical forces. p130Cas/BCAR1 plays a role in cell transformation and cancer progression and alterations of p130Cas/BCAR1 expression and the resulting activation of selective signalling are determinants for the occurrence of different types of human tumors.

• PSTPIP1 and PSTPIP2 (Proline-serine-threonine phosphatase-interacting protein 1 and 2). PTPN12 interacts with and dephosphorylates the two proteins. The interactions are mediated by C-terminal region of PTPN12 [8, 9, 10, 11].

• c-Abl. c-Abl is a proto-oncogene encoding cytoplasmic and nuclear protein tyrosine kinase (ABL family in KinBase). It is implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. PTPN12 interacts with and dephosphorylates c-Abl via PSTPIP1. On the other hand, c-Abl phosphorylates PSTPIP1 [12].

• Insulin receptor (IR). IR plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. It is a tyrosine phosphatase of InsR family in KinBase [13].

• CSK?

• SHC1, SHC-transforming protein 1. SHC encodes three adaptor proteins, p66, p52, p46, transmit signaling of the cell surface receptors such as EGFR, erbV-2 and insulin receptors. The isoforms are different in domain combination and functions (domain combination picture and text). PTPN12/PTP-PEST interacts with p66 and p52 but not p46, which suggest the interaction is mediated by the C-terminal region of CH2 domain common in p66 and p52 but absent from p46 [14]. However, another study in mouse found the interaction between PTPN12 and SHCp52 was mediated by SHCp52 PTB domain and NPLH sequence in the C-terminus of murine PTP-PEST [15]. (note: synergy between PTB and CH2 domain?) The interaction is stimulated by activators of protein kinase C (PKC) [14].

• Cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) regulates PTPN12/PTP-PEST via phosphorylation at Ser-39 and Ser-435. Phosphorylation of Ser-39 in vitro decreases the phosphatase activity of by reducing its affinity for substrate [16].

PPTN12/PTP-PEST is implicated in cancer [17].

PTPN18 (BDP1/PTP-HSCF)

PTPN18 was first identified as Brain Derived Phosphatase (BDP1) [18]. According RNA-seq data from GTEx, PTPN18 is most abundantly expressed in spleen. In brain, it is most abundant in cerebellum at similar level with whole blodd, small intestine, prostate and transverse colon. Its expression in other parts of brain is much lower in comparison with the tissues above.

PTPN18 have below substrates and/or interacting partners:

• PSTPIP1 and PSTPIP2 (Proline-serine-threonine phosphatase-interacting protein 1 and 2). PTPN18 interacts with and dephosphorylates the two proteins. The interactions are mediated by C-terminal region of PTPN18 [8, 9, 10].

• c-Abl. c-Abl is a proto-oncogene encoding cytoplasmic and nuclear protein tyrosine kinase (ABL family in KinBase). It is implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. PTPN18 interacts with and dephosphorylates c-Abl via PSTPIP1. On the other hand, c-Abl phosphorylates PSTPIP1 [12].

• CSK. Like PTPN12 and PTPN22, PTPN18 interacts with CSK, too. However, the interaction is not mediated by CSK SH3 domain, instead by CSK SH2 domain [19].

• HER2/ErbB2? PTPN18 is a negative regulator of HER2/ErbB2 [20]. But it is unclear whether it dephosphorylates HER2/ErbB2, directly.

PTPN22 (LYP/PEP/PTPN8)

PTPN22 predominantly in hematopoietic tissues

PTPN22 (aka lymphoid tyrosine phosphatase, LYP) mainly functions in immune system, particularly its R620W variant associated with many autoimmune diseases. PTPN22 is expressed in certain tissues and cell types, including EBV-transformed lymphocytes, whole blood, spleen and small intestine - terminal ileum (GTEx). Northern blot analysis found PTPN22 to be expressed predominantly in hematopoietic tissue, including spleen, lymph node, thymus, peripheral blood leukocytes, bone marrow, and fetal liver [21], in consistent with earlier study [2].

PTPN22 is expressed in macrophages and plays a critical role in regulating macrophage activation and polarization [22].

R620W variant associated with multiple autoimmune diseases

Missense single-nucleotide polymorphism (SNP) R620W is associated with different autoimmune diseases [23, 24, 25, 26], including rheumatoid arthritis (RA) [27, 28, 29, 30], systemic lupus erythematosus (SLE) [29, 31, 32], type 1 diabetes (T1D) [23], Hashimoto thyroiditis [23], juvenile idiopathic arthritis (JIA) [33], Grave's disease (GD) [33]. However, multiple sclerosis (MS) did not show association with R620W [23].

PTPN22 R620W variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients, and PTPN22 R620W has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation [34, 35]. Thus, R620W is a gain-of-function mutant.

One model behind is as following. R620 locates in a proline-rich sequence in PTPN22, which mediates the interaction between PTPN22 and tyrosine kinase CSK. The R620W variation disrupts not only the interaction between PTPN22 and CSK, but also that between PTPN22 and PTPN22's substrate Src kinase Lck, since PTPN22 constitutively interacts with Lck in a CSK-dependent manner. Lck is not only the substrate of PTPN22, but also phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [36]. Thus, the R620W variation disrupts the interaction between PTPN22 and Lck, leading to reduced phosphorylation at Tyr-536 of PTPN22, which ultimately contributes to gain-of-function inhibition of T cell signaling [36].

Substrates

• Lck (lymphocyte-specific protein tyrosine kinase), a protein found inside specialized cells of the immune system called lymphocytes. Native PTPN22 dephosphorylated Lck at its activating tyrosine residue Tyr-394, but not at the regulatory tyrosine Tyr-505 [37]. On the other hand, Lck phosphorylates PTPN22 at Tyr-536, playing an inhibitory role on the phosphatase activity [36]. Lck is a member of TK group, Src family and SrcB subfamily according to KinBase. Other members in SrcB include LYN, BLK and HCK (note: can they be PTPN22's substrates?).

• ZAP70 (Zeta-chain-associated protein kinase 70), a protein normally expressed near the surface membrane of T cells and natural killer cells. It is part of the T cell receptor, and plays a critical role in T-cell signaling. Native PTPN22 dephosphorylated ZAP70 at its activating tyrosine residue Tyr-493, but not at the regulatory tyrosine Tyr-319 [37]. ZAP70 is a member of TK group, Syk family in KinBase. Another member in Syk family is SYK (note: can it be PTPN22's substrates?).

• VAV, a proto-oncogene that is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. The protein is important in hematopoiesis, playing a role in T-cell and B-cell development and activation [37].

• CD3epsilon, together with CD3-gamma, -delta and -zeta, and the T-cell receptor alpha/beta and gamma/delta heterodimers, forms the T cell receptor-CD3 complex. This complex plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways [37].

• T cell antigen receptor (TCR) zeta, a subunit of T cell receptor-CD3 complex. It plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways [37].

• SKAP2 (Src kinase-associated phosphoprotein 2) [38]

• Valosin containing protein. a type II member of AAA+-ATPase family. It functions as a ubiquitin segregase that remodels multimeric protein complexes by extracting polyubiquitinated proteins for recycling or degradation by the proteasome [37].

Interacting partners

CSK forms a complex with PTPN22 and Lck via PTPN22's proline-rich sequence and CSK's SH3 domain [39, 40]. Both CSK and Lck are tyrosine phosphatase: CSK is tyrosine kinase group, CSK family; Lck is Src kinase group, Lck family in KinBase.

adaptor molecule Grb2 binds to PTPN22 via Grb2's N-terminal SH3 domain [21]. (SH3 bind to proline-rich sequence of PTPN22?)

PKC regulates PTPN22/LYP by serine phosphorylation. PTPN22 is phosphorylated exclusively at Ser-35 by PKC both in vitro and in vivo. The status of Ser-35 phosphorylation may dictate the conformational state of the insert region and thus PTPN22 substrate recognition. Ser-35 phosphorylation impairs PTPN22 to inactivate the Src family kinases and down-regulate T cell receptor signaling [41].

Here are some interesting papers have been incorporated into this page [42, 43, 44, 45, 46, 47, 48].

References

1. Tsai SJ, Sen U, Zhao L, Greenleaf WB, Dasgupta J, Fiorillo E, Orrú V, Bottini N, and Chen XS. Crystal structure of the human lymphoid tyrosine phosphatase catalytic domain: insights into redox regulation . Biochemistry. 2009 Jun 9;48(22):4838-45. DOI:10.1021/bi900166y | PubMed ID:19371084 | HubMed [Tsai09]
2. Cohen S, Dadi H, Shaoul E, Sharfe N, and Roifman CM. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood. 1999 Mar 15;93(6):2013-24. PubMed ID:10068674 | HubMed [Cohen99]
3. Liu Y, Stanford SM, Jog SP, Fiorillo E, Orrú V, Comai L, and Bottini N. Regulation of lymphoid tyrosine phosphatase activity: inhibition of the catalytic domain by the proximal interdomain. Biochemistry. 2009 Aug 11;48(31):7525-32. DOI:10.1021/bi900332f | PubMed ID:19586056 | HubMed [Liu09]
4. Yi T, Cleveland JL, and Ihle JN. Identification of novel protein tyrosine phosphatases of hematopoietic cells by polymerase chain reaction amplification. Blood. 1991 Nov 1;78(9):2222-8. PubMed ID:1932742 | HubMed [Yi91]
5. Takekawa M, Itoh F, Hinoda Y, Arimura Y, Toyota M, Sekiya M, Adachi M, Imai K, and Yachi A. Cloning and characterization of a human cDNA encoding a novel putative cytoplasmic protein-tyrosine-phosphatase. Biochem Biophys Res Commun. 1992 Dec 15;189(2):1223-30. DOI:10.1016/0006-291x(92)92335-u | PubMed ID:1472029 | HubMed [Takekawa92]
6. Yang Q, Co D, Sommercorn J, and Tonks NK. Cloning and expression of PTP-PEST. A novel, human, nontransmembrane protein tyrosine phosphatase. J Biol Chem. 1993 Mar 25;268(9):6622-8. PubMed ID:8454633 | HubMed [Yang93]
7. Garton AJ, Flint AJ, and Tonks NK. Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST. Mol Cell Biol. 1996 Nov;16(11):6408-18. DOI:10.1128/MCB.16.11.6408 | PubMed ID:8887669 | HubMed [Garton96]
8. Spencer S, Dowbenko D, Cheng J, Li W, Brush J, Utzig S, Simanis V, and Lasky LA. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for a PEST tyrosine phosphatase. J Cell Biol. 1997 Aug 25;138(4):845-60. DOI:10.1083/jcb.138.4.845 | PubMed ID:9265651 | HubMed [Spencer97]
9. Dowbenko D, Spencer S, Quan C, and Lasky LA. Identification of a novel polyproline recognition site in the cytoskeletal associated protein, proline serine threonine phosphatase interacting protein. J Biol Chem. 1998 Jan 9;273(2):989-96. DOI:10.1074/jbc.273.2.989 | PubMed ID:9422760 | HubMed [Dowbenko98]
10. Wu Y, Dowbenko D, and Lasky LA. PSTPIP 2, a second tyrosine phosphorylated, cytoskeletal-associated protein that binds a PEST-type protein-tyrosine phosphatase. J Biol Chem. 1998 Nov 13;273(46):30487-96. DOI:10.1074/jbc.273.46.30487 | PubMed ID:9804817 | HubMed [Wu98]
11. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R, Bashiardes S, and Lovett M. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002 Apr 15;11(8):961-9. DOI:10.1093/hmg/11.8.961 | PubMed ID:11971877 | HubMed [Wise02]
12. Cong F, Spencer S, Côté JF, Wu Y, Tremblay ML, Lasky LA, and Goff SP. Cytoskeletal protein PSTPIP1 directs the PEST-type protein tyrosine phosphatase to the c-Abl kinase to mediate Abl dephosphorylation. Mol Cell. 2000 Dec;6(6):1413-23. DOI:10.1016/s1097-2765(00)00138-6 | PubMed ID:11163214 | HubMed [Cong00]
14. Habib T, Herrera R, and Decker SJ. Activators of protein kinase C stimulate association of Shc and the PEST tyrosine phosphatase. J Biol Chem. 1994 Oct 14;269(41):25243-6. PubMed ID:7929214 | HubMed [Habib94]
15. Charest A, Wagner J, Jacob S, McGlade CJ, and Tremblay ML. Phosphotyrosine-independent binding of SHC to the NPLH sequence of murine protein-tyrosine phosphatase-PEST. Evidence for extended phosphotyrosine binding/phosphotyrosine interaction domain recognition specificity. J Biol Chem. 1996 Apr 5;271(14):8424-9. DOI:10.1074/jbc.271.14.8424 | PubMed ID:8626541 | HubMed [Charest94]
16. Garton AJ and Tonks NK. PTP-PEST: a protein tyrosine phosphatase regulated by serine phosphorylation. EMBO J. 1994 Aug 15;13(16):3763-71. DOI:10.1002/j.1460-2075.1994.tb06687.x | PubMed ID:7520867 | HubMed [Garton94]
17. Takekawa M, Itoh F, Hinoda Y, Adachi M, Ariyama T, Inazawa J, Imai K, and Yachi A. Chromosomal localization of the protein tyrosine phosphatase G1 gene and characterization of the aberrant transcripts in human colon cancer cells. FEBS Lett. 1994 Feb 21;339(3):222-8. DOI:10.1016/0014-5793(94)80420-6 | PubMed ID:7509295 | HubMed [Takekawa94]
18. Kim YW, Wang H, Sures I, Lammers R, Martell KJ, and Ullrich A. Characterization of the PEST family protein tyrosine phosphatase BDP1. Oncogene. 1996 Nov 21;13(10):2275-9. PubMed ID:8950995 | HubMed [Kim96]
19. Wang B, Lemay S, Tsai S, and Veillette A. SH2 domain-mediated interaction of inhibitory protein tyrosine kinase Csk with protein tyrosine phosphatase-HSCF. Mol Cell Biol. 2001 Feb;21(4):1077-88. DOI:10.1128/MCB.21.4.1077-1088.2001 | PubMed ID:11158295 | HubMed [Wang01]
20. Gensler M, Buschbeck M, and Ullrich A. Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1. J Biol Chem. 2004 Mar 26;279(13):12110-6. DOI:10.1074/jbc.M309527200 | PubMed ID:14660651 | HubMed [Gensler04]
21. Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, and Jallal B. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol. 2002 Mar;30(3):237-44. DOI:10.1016/s0301-472x(01)00794-9 | PubMed ID:11882361 | HubMed [Hill02]
22. Chang HH, Miaw SC, Tseng W, Sun YW, Liu CC, Tsao HW, and Ho IC. PTPN22 modulates macrophage polarization and susceptibility to dextran sulfate sodium-induced colitis. J Immunol. 2013 Sep 1;191(5):2134-43. DOI:10.4049/jimmunol.1203363 | PubMed ID:23913970 | HubMed [Chang13]
23. Criswell LA, Pfeiffer KA, Lum RF, Gonzales B, Novitzke J, Kern M, Moser KL, Begovich AB, Carlton VE, Li W, Lee AT, Ortmann W, Behrens TW, and Gregersen PK. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005 Apr;76(4):561-71. DOI:10.1086/429096 | PubMed ID:15719322 | HubMed [Criswell05]
24. Bottini N, Vang T, Cucca F, and Mustelin T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol. 2006 Aug;18(4):207-13. DOI:10.1016/j.smim.2006.03.008 | PubMed ID:16697661 | HubMed [Bottini06]
25. Vang T, Miletic AV, Bottini N, and Mustelin T. Protein tyrosine phosphatase PTPN22 in human autoimmunity. Autoimmunity. 2007 Sep;40(6):453-61. DOI:10.1080/08916930701464897 | PubMed ID:17729039 | HubMed [Vang07]
26. Stanford SM and Bottini N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheumatol. 2014 Oct;10(10):602-11. DOI:10.1038/nrrheum.2014.109 | PubMed ID:25003765 | HubMed [Stanford14]
27. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, Ardlie KG, Huang Q, Smith AM, Spoerke JM, Conn MT, Chang M, Chang SY, Saiki RK, Catanese JJ, Leong DU, Garcia VE, McAllister LB, Jeffery DA, Lee AT, Batliwalla F, Remmers E, Criswell LA, Seldin MF, Kastner DL, Amos CI, Sninsky JJ, and Gregersen PK. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004 Aug;75(2):330-7. DOI:10.1086/422827 | PubMed ID:15208781 | HubMed [Begovich04]
28. Plenge RM, Padyukov L, Remmers EF, Purcell S, Lee AT, Karlson EW, Wolfe F, Kastner DL, Alfredsson L, Altshuler D, Gregersen PK, Klareskog L, and Rioux JD. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am J Hum Genet. 2005 Dec;77(6):1044-60. DOI:10.1086/498651 | PubMed ID:16380915 | HubMed [Plenge05]
29. Orozco G, Sánchez E, González-Gay MA, López-Nevot MA, Torres B, Cáliz R, Ortego-Centeno N, Jiménez-Alonso J, Pascual-Salcedo D, Balsa A, de Pablo R, Nuñez-Roldan A, González-Escribano MF, and Martín J. Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 2005 Jan;52(1):219-24. DOI:10.1002/art.20771 | PubMed ID:15641066 | HubMed [Orozco05]
30. Michou L, Lasbleiz S, Rat AC, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Pierlot C, Glikmans E, Garnier S, Dausset J, Vaz C, Fernandes M, Petit-Teixeira E, Lemaire I, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Lopes-Vaz A, Prum B, Bardin T, Dieudé P, Cornélis F, and European Consortium on Rheumatoid Arthritis Families. Linkage proof for PTPN22, a rheumatoid arthritis susceptibility gene and a human autoimmunity gene. Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1649-54. DOI:10.1073/pnas.0610250104 | PubMed ID:17237219 | HubMed [Michou07]
31. Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, and Behrens TW. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004 Sep;75(3):504-7. DOI:10.1086/423790 | PubMed ID:15273934 | HubMed [Kyogoku04]
32. Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L, Barratt BJ, Guja C, Ionescu-Tîrgoviste C, Savage DA, Dunger DB, Widmer B, Strachan DP, Ring SM, Walker N, Clayton DG, Twells RC, Gough SC, and Todd JA. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes. 2004 Nov;53(11):3020-3. DOI:10.2337/diabetes.53.11.3020 | PubMed ID:15504986 | HubMed [Smyth04]
33. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, and Harley JB. The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. Rheumatology (Oxford). 2007 Jan;46(1):49-56. DOI:10.1093/rheumatology/kel170 | PubMed ID:16760194 | HubMed [Lee07]
34. Vang T, Congia M, Macis MD, Musumeci L, Orrú V, Zavattari P, Nika K, Tautz L, Taskén K, Cucca F, Mustelin T, and Bottini N. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005 Dec;37(12):1317-9. DOI:10.1038/ng1673 | PubMed ID:16273109 | HubMed [Vang05]
35. Aarnisalo J, Treszl A, Svec P, Marttila J, Oling V, Simell O, Knip M, Körner A, Madacsy L, Vasarhelyi B, Ilonen J, and Hermann R. Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant. J Autoimmun. 2008 Aug;31(1):13-21. DOI:10.1016/j.jaut.2008.01.001 | PubMed ID:18299186 | HubMed [Aarnisalo08]
36. Fiorillo E, Orrú V, Stanford SM, Liu Y, Salek M, Rapini N, Schenone AD, Saccucci P, Delogu LG, Angelini F, Manca Bitti ML, Schmedt C, Chan AC, Acuto O, and Bottini N. Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J Biol Chem. 2010 Aug 20;285(34):26506-18. DOI:10.1074/jbc.M110.111104 | PubMed ID:20538612 | HubMed [Fiorillo10]
37. Wu J, Katrekar A, Honigberg LA, Smith AM, Conn MT, Tang J, Jeffery D, Mortara K, Sampang J, Williams SR, Buggy J, and Clark JM. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 2006 Apr 21;281(16):11002-10. DOI:10.1074/jbc.M600498200 | PubMed ID:16461343 | HubMed [Wu06]
38. Yu X, Chen M, Zhang S, Yu ZH, Sun JP, Wang L, Liu S, Imasaki T, Takagi Y, and Zhang ZY. Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and identification of Src kinase-associated protein of 55 kDa homolog (SKAP-HOM) as a Lyp substrate. J Biol Chem. 2011 Sep 2;286(35):30526-30534. DOI:10.1074/jbc.M111.254722 | PubMed ID:21719704 | HubMed [Yu11]
39. Gregorieff A, Cloutier JF, and Veillette A. Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk). J Biol Chem. 1998 May 22;273(21):13217-22. DOI:10.1074/jbc.273.21.13217 | PubMed ID:9582365 | HubMed [Gregorieff98]
40. de la Puerta ML, Trinidad AG, Rodríguez Mdel C, de Pereda JM, Sánchez Crespo M, Bayón Y, and Alonso A. The autoimmunity risk variant LYP-W620 cooperates with CSK in the regulation of TCR signaling. PLoS One. 2013;8(1):e54569. DOI:10.1371/journal.pone.0054569 | PubMed ID:23359562 | HubMed [delaPuerta13]
41. Yu X, Sun JP, He Y, Guo X, Liu S, Zhou B, Hudmon A, and Zhang ZY. Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19767-72. DOI:10.1073/pnas.0706233104 | PubMed ID:18056643 | HubMed [Yu07]
42. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, and Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?. FEBS Lett. 2011 Dec 1;585(23):3689-98. DOI:10.1016/j.febslet.2011.04.032 | PubMed ID:21515266 | HubMed [Burn11]
43. Menard L, Saadoun D, Isnardi I, Ng YS, Meyers G, Massad C, Price C, Abraham C, Motaghedi R, Buckner JH, Gregersen PK, and Meffre E. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J Clin Invest. 2011 Sep;121(9):3635-44. DOI:10.1172/JCI45790 | PubMed ID:21804190 | HubMed [Menard11]
44. Chien W, Tidow N, Williamson EA, Shih LY, Krug U, Kettenbach A, Fermin AC, Roifman CM, and Koeffler HP. Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway. J Biol Chem. 2003 Jul 25;278(30):27413-20. DOI:10.1074/jbc.M304575200 | PubMed ID:12764153 | HubMed [Chien03]
45. Chang HH, Tai TS, Lu B, Iannaccone C, Cernadas M, Weinblatt M, Shadick N, Miaw SC, and Ho IC. PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. PLoS One. 2012;7(3):e33067. DOI:10.1371/journal.pone.0033067 | PubMed ID:22427951 | HubMed [Chang12]
46. Negro R, Gobessi S, Longo PG, He Y, Zhang ZY, Laurenti L, and Efremov DG. Overexpression of the autoimmunity-associated phosphatase PTPN22 promotes survival of antigen-stimulated CLL cells by selectively activating AKT. Blood. 2012 Jun 28;119(26):6278-87. DOI:10.1182/blood-2012-01-403162 | PubMed ID:22569400 | HubMed [Negro12]
47. Vang T, Landskron J, Viken MK, Oberprieler N, Torgersen KM, Mustelin T, Tasken K, Tautz L, Rickert RC, and Lie BA. The autoimmune-predisposing variant of lymphoid tyrosine phosphatase favors T helper 1 responses. Hum Immunol. 2013 May;74(5):574-85. DOI:10.1016/j.humimm.2012.12.017 | PubMed ID:23333624 | HubMed [Vang13]
48. Wu DJ, Zhou W, Enouz S, Orrú V, Stanford SM, Maine CJ, Rapini N, Sawatzke K, Engel I, Fiorillo E, Sherman LA, Kronenberg M, Zehn D, Peterson E, and Bottini N. Autoimmunity-associated LYP-W620 does not impair thymic negative selection of autoreactive T cells. PLoS One. 2014;9(2):e86677. DOI:10.1371/journal.pone.0086677 | PubMed ID:24498279 | HubMed [Wu14]

Supplementary information

Below are the sequences used for position.

>hs_PTPN12 MEQVEILRKFIQRVQAMKSPDHNGEDNFARDFMRLRRLSTKYRTEKIYPTATGEKEENVKKNRYKDILPFDHSRVKLTLKTPSQDSDYINANFIKGVYGPKAYVATQGPLANTVIDFWRMIWEYNVVIIVMACREFEMGRKKCERYWPLYGEDPITFAPFKISCEDEQARTDYFIRTLLLEFQNESRRLYQFHYVNWPDHDVPSSFDSILDMISLMRKYQEHEDVPICIHCSAGCGRTGAICAIDYTWNLLKAGKIPEEFNVFNLIQEMRTQRHSAVQTKEQYELVHRAIAQLFEKQLQLYEIHGAQKIADGVNEINTENMVSSIEPEKQDSPPPKPPRTRSCLVEGDAKEEILQPPEPHPVPPILTPSPPSAFPTVTTVWQDNDRYHPKPVLHMVSSEQHSADLNRNYSKSTELPGKNESTIEQIDKKLERNLSFEIKKVPLQEGPKSFDGNTLLNRGHAIKIKSASPCIADKISKPQELSSDLNVGDTSQNSCVDCSVTQSNKVSVTPPEESQNSDTPPRPDRLPLDEKGHVTWSFHGPENAIPIPDLSEGNSSDINYQTRKTVSLTPSPTTQVETPDLVDHDNTSPLFRTPLSFTNPLHSDDSDSDERNSDGAVTQNKTNISTASATVSAATSTESISTRKVLPMSIARHNIAGTTHSGAEKDVDVSEDSPPPLPERTPESFVLASEHNTPVRSEWSELQSQERSEQKKSEGLITSENEKCDHPAGGIHYEMCIECPPTFSDKREQISENPTEATDIGFGNRCGKPKGPRDPPSEWT

>hs_PTPN22 MDQREILQKFLDEAQSKKITKEEFANEFLKLKRQSTKYKADKTYPTTVAEKPKNIKKNRYKDILPYDYSRVELSLITSDEDSSYINANFIKGVYGPKAYIATQGPLSTTLLDFWRMIWEYSVLIIVMACMEYEMGKKKCERYWAEPGEMQLEFGPFSVSCEAEKRKSDYIIRTLKVKFNSETRTIYQFHYKNWPDHDVPSSIDPILELIWDVRCYQEDDSVPICIHCSAGCGRTGVICAIDYTWMLLKDGIIPENFSVFSLIREMRTQRPSLVQTQEQYELVYNAVLELFKRQMDVIRDKHSGTESQAKHCIPEKNHTLQADSYSPNLPKSTTKAAKMMNQQRTKMEIKESSSFDFRTSEISAKEELVLHPAKSSTSFDFLELNYSFDKNADTTMKWQTKAFPIVGEPLQKHQSLDLGSLLFEGCSNSKPVNAAGRYFNSKVPITRTKSTPFELIQQRETKEVDSKENFSYLESQPHDSCFVEMQAQKVMHVSSAELNYSLPYDSKHQIRNASNVKHHDSSALGVYSYIPLVENPYFSSWPPSGTSSKMSLDLPEKQDGTVFPSSLLPTSSTSLFSYYNSHDSLSLNSPTNISSLLNQESAVLATAPRIDDEIPPPLPVRTPESFIVVEEAGEFSPNVPKSLSSAVKVKIGTSLEWGGTSEPKKFDDSVILRPSKSVKLRSPKSELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIETYSTSYPDTMENSTSSKQTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNSSSFLNFGFANRFSKPKGPRNPPPTWNI