ID PTN22_HUMAN Reviewed; 807 AA. AC Q9Y2R2; A0N0K6; B1ALC8; D4NZ71; E9PLD8; E9PPI1; O95063; O95064; Q6IPX8; AC Q8WVM1; DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot. DT 27-MAR-2002, sequence version 2. DT 24-JAN-2024, entry version 194. DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 22; DE EC=3.1.3.48 {ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:27043286}; DE AltName: Full=Hematopoietic cell protein-tyrosine phosphatase 70Z-PEP; DE AltName: Full=Lymphoid phosphatase; DE Short=LyP; DE AltName: Full=PEST-domain phosphatase; DE Short=PEP; GN Name=PTPN22; Synonyms=PTPN8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND INTERACTION WITH CBL. RX PubMed=10068674; RA Cohen S., Dadi H., Shaoul E., Sharfe N., Roifman C.M.; RT "Cloning and characterization of a lymphoid-specific, inducible human RT protein tyrosine phosphatase, Lyp."; RL Blood 93:2013-2024(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT TRP-620. RX PubMed=21044313; DOI=10.1186/1471-2199-11-78; RA Wang S., Dong H., Han J., Ho W.T., Fu X., Zhao Z.J.; RT "Identification of a variant form of tyrosine phosphatase LYP."; RL BMC Mol. Biol. 11:78-78(2010). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT TRP-620. RA Liu T., Zhang J., Fu G., Zhang Q., Ye M., Zhou J., Wu J., Shen Y., Yu M., RA Chen S., Mao M., Chen Z.; RT "Human protein tyrosine phosphatase (70zpep) homolog."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Livingston R.J., Shaffer T., McFarland I., Nguyen C.P., Stanaway I.B., RA Rajkumar N., Johnson E.J., da Ponte S.H., Willa H., Ahearn M.O., RA Bertucci C., Acklestad J., Carroll A., Swanson J., Gildersleeve H.I., RA Nickerson D.A.; RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT TRP-620. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT TRP-620. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5). RC TISSUE=Lymph; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION. RX PubMed=16461343; DOI=10.1074/jbc.m600498200; RA Wu J., Katrekar A., Honigberg L.A., Smith A.M., Conn M.T., Tang J., RA Jeffery D., Mortara K., Sampang J., Williams S.R., Buggy J., Clark J.M.; RT "Identification of substrates of human protein-tyrosine phosphatase RT PTPN22."; RL J. Biol. Chem. 281:11002-11010(2006). RN [10] RP REVIEW ON FUNCTION. RX PubMed=17729039; DOI=10.1080/08916930701464897; RA Vang T., Miletic A.V., Bottini N., Mustelin T.; RT "Protein tyrosine phosphatase PTPN22 in human autoimmunity."; RL Autoimmunity 40:453-461(2007). RN [11] RP ALTERNATIVE SPLICING (ISOFORM 6). RX PubMed=22427951; DOI=10.1371/journal.pone.0033067; RA Chang H.H., Tai T.S., Lu B., Iannaccone C., Cernadas M., Weinblatt M., RA Shadick N., Miaw S.C., Ho I.C.; RT "PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of RT rheumatoid arthritis."; RL PLoS ONE 7:E33067-E33067(2012). RN [12] RP FUNCTION, AND INTERACTION WITH TRAF3. RX PubMed=23871208; DOI=10.1016/j.immuni.2013.06.013; RA Wang Y., Shaked I., Stanford S.M., Zhou W., Curtsinger J.M., Mikulski Z., RA Shaheen Z.R., Cheng G., Sawatzke K., Campbell A.M., Auger J.L., Bilgic H., RA Shoyama F.M., Schmeling D.O., Balfour H.H. Jr., Hasegawa K., Chan A.C., RA Corbett J.A., Binstadt B.A., Mescher M.F., Ley K., Bottini N., RA Peterson E.J.; RT "The autoimmunity-associated gene PTPN22 potentiates toll-like receptor- RT driven, type 1 interferon-dependent immunity."; RL Immunity 39:111-122(2013). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-449, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [14] RP FUNCTION. RX PubMed=23991106; DOI=10.1371/journal.pone.0072384; RA Spalinger M.R., Lang S., Vavricka S.R., Fried M., Rogler G., Scharl M.; RT "Protein tyrosine phosphatase non-receptor type 22 modulates NOD2-induced RT cytokine release and autophagy."; RL PLoS ONE 8:E72384-E72384(2013). RN [15] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=27043286; DOI=10.1172/jci83669; RA Spalinger M.R., Kasper S., Gottier C., Lang S., Atrott K., Vavricka S.R., RA Scharl S., Raselli T., Frey-Wagner I., Gutte P.M., Gruetter M.G., RA Beer H.D., Contassot E., Chan A.C., Dai X., Rawlings D.J., Mair F., RA Becher B., Falk W., Fried M., Rogler G., Scharl M.; RT "NLRP3 tyrosine phosphorylation is controlled by protein tyrosine RT phosphatase PTPN22."; RL J. Clin. Invest. 126:1783-1800(2016). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-294 IN COMPLEX WITH INHIBITOR, RP FUNCTION, PHOSPHORYLATION AT SER-35, AND MUTAGENESIS OF SER-35 AND THR-36. RX PubMed=18056643; DOI=10.1073/pnas.0706233104; RA Yu X., Sun J.P., He Y., Guo X., Liu S., Zhou B., Hudmon A., Zhang Z.Y.; RT "Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific RT tyrosine phosphatase implicated in autoimmune diseases."; RL Proc. Natl. Acad. Sci. U.S.A. 104:19767-19772(2007). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-302, DISULFIDE BOND, AND RP MUTAGENESIS OF CYS-129 AND CYS-231. RX PubMed=19371084; DOI=10.1021/bi900166y; RA Tsai S.J., Sen U., Zhao L., Greenleaf W.B., Dasgupta J., Fiorillo E., RA Orru V., Bottini N., Chen X.S.; RT "Crystal structure of the human lymphoid tyrosine phosphatase catalytic RT domain: insights into redox regulation."; RL Biochemistry 48:4838-4845(2009). RN [18] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-302, AND FUNCTION. RX PubMed=19167335; DOI=10.1016/j.cell.2008.11.038; RA Barr A.J., Ugochukwu E., Lee W.H., King O.N.F., Filippakopoulos P., RA Alfano I., Savitsky P., Burgess-Brown N.A., Mueller S., Knapp S.; RT "Large-scale structural analysis of the classical human protein tyrosine RT phosphatome."; RL Cell 136:352-363(2009). RN [19] RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 2-309 OF WILD TYPE AND VARIANT RP GLN-263, VARIANT GLN-263, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF RP VARIANT GLN-263. RX PubMed=18981062; DOI=10.1093/hmg/ddn363; RA Orru V., Tsai S.J., Rueda B., Fiorillo E., Stanford S.M., Dasgupta J., RA Hartiala J., Zhao L., Ortego-Centeno N., D'Alfonso S., Arnett F.C., Wu H., RA Gonzalez-Gay M.A., Tsao B.P., Pons-Estel B., Alarcon-Riquelme M.E., He Y., RA Zhang Z.Y., Allayee H., Chen X.S., Martin J., Bottini N., Danieli M.G., RA Galeazzi M., Sabbadini M.G., Migliaresi S., Sebastiani G.D.; RT "A loss-of-function variant of PTPN22 is associated with reduced risk of RT systemic lupus erythematosus."; RL Hum. Mol. Genet. 18:569-579(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-310 IN COMPLEX WITH SUBSTRATE. RA Seidel R.D., Love J., Piserchio A., Cowburn D.; RT "Lyp/PTPN22 phosphatase domain: substrate recognition and specificity for RT Src family kinases."; RL Submitted (DEC-2009) to the PDB data bank. RN [21] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-294 OF MUTANT SER-227 ALONE AND RP IN COMPLEX WITH SKAP2 PEPTIDE, SUBSTRATE SPECIFICITY, AND FUNCTION. RX PubMed=21719704; DOI=10.1074/jbc.m111.254722; RA Yu X., Chen M., Zhang S., Yu Z.H., Sun J.P., Wang L., Liu S., Imasaki T., RA Takagi Y., Zhang Z.Y.; RT "Substrate specificity of lymphoid-specific tyrosine phosphatase (Lyp) and RT identification of Src kinase-associated protein of 55 kDa homolog (SKAP- RT HOM) as a Lyp substrate."; RL J. Biol. Chem. 286:30526-30534(2011). RN [22] RP VARIANT TRP-620, INVOLVEMENT IN RA, INTERACTION WITH CSK, AND TISSUE RP SPECIFICITY. RX PubMed=15208781; DOI=10.1086/422827; RA Begovich A.B., Carlton V.E., Honigberg L.A., Schrodi S.J., RA Chokkalingam A.P., Alexander H.C., Ardlie K.G., Huang Q., Smith A.M., RA Spoerke J.M., Conn M.T., Chang M., Chang S.Y., Saiki R.K., Catanese J.J., RA Leong D.U., Garcia V.E., McAllister L.B., Jeffery D.A., Lee A.T., RA Batliwalla F., Remmers E., Criswell L.A., Seldin M.F., Kastner D.L., RA Amos C.I., Sninsky J.J., Gregersen P.K.; RT "A missense single-nucleotide polymorphism in a gene encoding a protein RT tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis."; RL Am. J. Hum. Genet. 75:330-337(2004). RN [23] RP VARIANT TRP-620, AND INVOLVEMENT IN SLE. RX PubMed=15273934; DOI=10.1086/423790; RA Kyogoku C., Langefeld C.D., Ortmann W.A., Lee A., Selby S., Carlton V.E.H., RA Chang M., Ramos P., Baechler E.C., Batliwalla F.M., Novitzke J., RA Williams A.H., Gillett C., Rodine P., Graham R.R., Ardlie K.G., RA Gaffney P.M., Moser K.L., Petri M., Begovich A.B., Gregersen P.K., RA Behrens T.W.; RT "Genetic association of the R620W polymorphism of protein tyrosine RT phosphatase PTPN22 with human SLE."; RL Am. J. Hum. Genet. 75:504-507(2004). RN [24] RP VARIANT TRP-620, INVOLVEMENT IN T1D, AND CHARACTERIZATION OF VARIANT RP TRP-620. RX PubMed=15004560; DOI=10.1038/ng1323; RA Bottini N., Musumeci L., Alonso A., Rahmouni S., Nika K., Rostamkhani M., RA MacMurray J., Meloni G.F., Lucarelli P., Pellecchia M., Eisenbarth G.S., RA Comings D., Mustelin T.; RT "A functional variant of lymphoid tyrosine phosphatase is associated with RT type I diabetes."; RL Nat. Genet. 36:337-338(2004). RN [25] RP VARIANT TRP-620. RX PubMed=15531553; DOI=10.1210/jc.2004-1108; RA Velaga M.R., Wilson V., Jennings C.E., Owen C.J., Herington S., RA Donaldson P.T., Ball S.G., James R.A., Quinton R., Perros P., Pearce S.H.; RT "The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) RT gene is a major determinant of Graves' disease."; RL J. Clin. Endocrinol. Metab. 89:5862-5865(2004). RN [26] RP VARIANT TRP-620. RX PubMed=15719322; DOI=10.1086/429096; RA Criswell L.A., Pfeiffer K.A., Lum R.F., Gonzales B., Novitzke J., Kern M., RA Moser K.L., Begovich A.B., Carlton V.E., Li W., Lee A.T., Ortmann W., RA Behrens T.W., Gregersen P.K.; RT "Analysis of families in the multiple autoimmune disease genetics RT consortium (MADGC) collection: the PTPN22 620W allele associates with RT multiple autoimmune phenotypes."; RL Am. J. Hum. Genet. 76:561-571(2005). RN [27] RP VARIANT TRP-620, AND INVOLVEMENT IN VTLG. RX PubMed=16015369; DOI=10.1038/sj.gene.6364243; RA Canton I., Akhtar S., Gavalas N.G., Gawkrodger D.J., Blomhoff A., RA Watson P.F., Weetman A.P., Kemp E.H.; RT "A single-nucleotide polymorphism in the gene encoding lymphoid protein RT tyrosine phosphatase (PTPN22) confers susceptibility to generalised RT vitiligo."; RL Genes Immun. 6:584-587(2005). RN [28] RP VARIANT TRP-620, AND CHARACTERIZATION OF VARIANT TRP-620. RX PubMed=19265110; DOI=10.4049/jimmunol.0713370; RA Arechiga A.F., Habib T., He Y., Zhang X., Zhang Z.Y., Funk A., RA Buckner J.H.; RT "Cutting edge: the PTPN22 allelic variant associated with autoimmunity RT impairs B cell signaling."; RL J. Immunol. 182:3343-3347(2009). RN [29] RP VARIANTS GLN-263 AND TRP-620, AND CHARACTERIZATION OF VARIANTS GLN-263 AND RP TRP-620. RX PubMed=21287672; DOI=10.1002/ibd.21630; RA Diaz-Gallo L.M., Espino-Paisan L., Fransen K., Gomez-Garcia M., RA van Sommeren S., Cardena C., Rodrigo L., Mendoza J.L., Taxonera C., RA Nieto A., Alcain G., Cueto I., Lopez-Nevot M.A., Bottini N., Barclay M.L., RA Crusius J.B., van Bodegraven A.A., Wijmenga C., Ponsioen C.Y., Gearry R.B., RA Roberts R.L., Weersma R.K., Urcelay E., Merriman T.R., Alizadeh B.Z., RA Martin J.; RT "Differential association of two PTPN22 coding variants with Crohn's RT disease and ulcerative colitis."; RL Inflamm. Bowel Dis. 17:2287-2294(2011). RN [30] RP VARIANTS PHE-201; GLN-263 AND TRP-266, AND CHARACTERIZATION OF VARIANTS RP PHE-201; GLN-263 AND TRP-266. RX PubMed=22952725; DOI=10.1371/journal.pone.0043631; RA Liu J., Chen M., Li R., Yang F., Shi X., Zhu L., Wang H.M., Yao W., Liu Q., RA Meng F.G., Sun J.P., Pang Q., Yu X.; RT "Biochemical and functional studies of lymphoid-specific tyrosine RT phosphatase (Lyp) variants S201F and R266W."; RL PLoS ONE 7:E43631-E43631(2012). CC -!- FUNCTION: Acts as a negative regulator of T-cell receptor (TCR) CC signaling by direct dephosphorylation of the Src family kinases LCK and CC FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and CC other key signaling molecules (PubMed:16461343, PubMed:18056643). CC Associates with and probably dephosphorylates CBL. Dephosphorylates LCK CC at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates CC ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). CC Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). CC Positively regulates toll-like receptor (TLR)-induced type 1 interferon CC production (PubMed:23871208). Promotes host antiviral responses CC mediated by type 1 interferon (By similarity). Regulates NOD2-induced CC pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). CC Acts as an activator of NLRP3 inflammasome assembly by mediating CC dephosphorylation of 'Tyr-861' of NLRP3 (PubMed:27043286). CC Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to CC anandamide (also called N-arachidonoylethanolamide) (By similarity). CC {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, CC ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, CC ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, CC ECO:0000269|PubMed:23991106, ECO:0000269|PubMed:27043286}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + CC phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:82620; EC=3.1.3.48; Evidence={ECO:0000255|PROSITE- CC ProRule:PRU10044, ECO:0000269|PubMed:21719704, CC ECO:0000269|PubMed:27043286}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine CC phosphate = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + CC phosphate; Xref=Rhea:RHEA:56532, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:131894; CC Evidence={ECO:0000250|UniProtKB:P29352}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56533; CC Evidence={ECO:0000250|UniProtKB:P29352}; CC -!- ACTIVITY REGULATION: Down-regulated by phosphorylation. CC -!- SUBUNIT: Interacts with CSK (PubMed:15208781). Interacts with LPXN (By CC similarity). Interacts with CBL (PubMed:10068674). Interacts with TRAF3 CC (via MATH domain); the interaction promotes TRAF3 polyubiquitination CC (PubMed:23871208). {ECO:0000250|UniProtKB:P29352, CC ECO:0000269|PubMed:10068674, ECO:0000269|PubMed:15208781, CC ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:21719704, CC ECO:0000269|PubMed:23871208, ECO:0000269|Ref.20}. CC -!- INTERACTION: CC Q9Y2R2; P20963: CD247; NbExp=4; IntAct=EBI-1211241, EBI-1165705; CC Q9Y2R2; P00533: EGFR; NbExp=3; IntAct=EBI-1211241, EBI-297353; CC Q9Y2R2; P62993: GRB2; NbExp=2; IntAct=EBI-1211241, EBI-401755; CC Q9Y2R2; P06239: LCK; NbExp=6; IntAct=EBI-1211241, EBI-1348; CC Q9Y2R2; O43586: PSTPIP1; NbExp=6; IntAct=EBI-1211241, EBI-1050964; CC Q9Y2R2; O75563: SKAP2; NbExp=3; IntAct=EBI-1211241, EBI-2483161; CC Q9Y2R2; Q13114: TRAF3; NbExp=2; IntAct=EBI-1211241, EBI-357631; CC Q9Y2R2; P43403: ZAP70; NbExp=4; IntAct=EBI-1211241, EBI-1211276; CC Q9Y2R2; Q3UND0: Skap2; Xeno; NbExp=2; IntAct=EBI-1211241, EBI-642769; CC Q9Y2R2; Q60803: Traf3; Xeno; NbExp=5; IntAct=EBI-1211241, EBI-520135; CC Q9Y2R2-1; O43586: PSTPIP1; NbExp=9; IntAct=EBI-6955492, EBI-1050964; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P29352}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=LyP1; CC IsoId=Q9Y2R2-1; Sequence=Displayed; CC Name=2; Synonyms=LyP2; CC IsoId=Q9Y2R2-2; Sequence=VSP_005134; CC Name=3; CC IsoId=Q9Y2R2-3; Sequence=VSP_039728; CC Name=4; Synonyms=LYP3; CC IsoId=Q9Y2R2-4; Sequence=VSP_039729; CC Name=5; CC IsoId=Q9Y2R2-5; Sequence=VSP_039725, VSP_039726, VSP_039727; CC Name=6; Synonyms=PTPN22.6; CC IsoId=Q9Y2R2-6; Sequence=VSP_044428, VSP_044429; CC -!- TISSUE SPECIFICITY: Expressed in bone marrow, B and T-cells, PBMCs, CC natural killer cells, monocytes, dendritic cells and neutrophils CC (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in CC lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and CC both mature B and T-cells. {ECO:0000269|PubMed:15208781}. CC -!- INDUCTION: By muramyl-dipeptide and lipopolysaccharide. CC {ECO:0000269|PubMed:23991106}. CC -!- PTM: Phosphorylation on Ser-35 by PKC/PRKCD abrogates its ability to CC dephosphorylate and inactivate the SRC family kinases. CC {ECO:0000269|PubMed:18056643}. CC -!- DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, CC relapsing, inflammatory, and often febrile multisystemic disorder of CC connective tissue, characterized principally by involvement of the CC skin, joints, kidneys and serosal membranes. It is of unknown etiology, CC but is thought to represent a failure of the regulatory mechanisms of CC the autoimmune system. The disease is marked by a wide range of system CC dysfunctions, an elevated erythrocyte sedimentation rate, and the CC formation of LE cells in the blood or bone marrow. CC {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- DISEASE: Type 1 diabetes mellitus (T1D) [MIM:222100]: A multifactorial CC disorder of glucose homeostasis that is characterized by susceptibility CC to ketoacidosis in the absence of insulin therapy. Clinical features CC are polydipsia, polyphagia and polyuria which result from CC hyperglycemia-induced osmotic diuresis and secondary thirst. These CC derangements result in long-term complications that affect the eyes, CC kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. CC Note=Disease susceptibility may be associated with variants affecting CC the gene represented in this entry. CC -!- DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory CC disease with autoimmune features and a complex genetic component. It CC primarily affects the joints and is characterized by inflammatory CC changes in the synovial membranes and articular structures, widespread CC fibrinoid degeneration of the collagen fibers in mesenchymal tissues, CC and by atrophy and rarefaction of bony structures. CC {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- DISEASE: Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the CC skin and mucous membranes. It is characterized by circumscribed CC depigmented macules and patches, commonly on extensor aspects of CC extremities, on the face or neck and in skin folds. Vitiligo is a CC progressive disorder in which some or all of the melanocytes in the CC affected skin are selectively destroyed. It is a multifactorial CC disorder with a complex etiology probably including autoimmune CC mechanisms, and is associated with an elevated risk of other autoimmune CC diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 2]: Due to intron retention. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 6]: Lacks most of the phosphatase domain and CC functions as a dominant negative isoform of the full length PTPN22. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family. Non- CC receptor class 4 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF001846; AAD00904.1; -; mRNA. DR EMBL; AF001847; AAD00905.1; -; mRNA. DR EMBL; GU479452; ADD59979.1; -; mRNA. DR EMBL; AF077031; AAD27764.1; -; mRNA. DR EMBL; AK310570; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; EF064714; ABK41897.1; -; Genomic_DNA. DR EMBL; AL137856; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471122; EAW56575.1; -; Genomic_DNA. DR EMBL; CH471122; EAW56576.1; -; Genomic_DNA. DR EMBL; BC017785; AAH17785.1; -; mRNA. DR EMBL; BC071670; AAH71670.1; -; mRNA. DR CCDS; CCDS863.1; -. [Q9Y2R2-1] DR CCDS; CCDS864.2; -. [Q9Y2R2-3] DR RefSeq; NP_001180360.1; NM_001193431.2. [Q9Y2R2-4] DR RefSeq; NP_001295226.1; NM_001308297.1. DR RefSeq; NP_036543.4; NM_012411.5. [Q9Y2R2-3] DR RefSeq; NP_057051.3; NM_015967.6. DR PDB; 2P6X; X-ray; 1.90 A; A/B=1-302. DR PDB; 2QCJ; X-ray; 3.00 A; A/B=1-294. DR PDB; 2QCT; X-ray; 2.80 A; A/B=1-294. DR PDB; 3BRH; X-ray; 2.20 A; A/B=1-310. DR PDB; 3H2X; X-ray; 2.20 A; A=1-302. DR PDB; 3OLR; X-ray; 2.50 A; A/B/C/D=1-294. DR PDB; 3OMH; X-ray; 2.90 A; A/B/C/D=1-294. DR PDB; 4J51; X-ray; 2.30 A; A/B=1-303. DR PDB; 7AAM; X-ray; 2.15 A; C=787-807. DR PDBsum; 2P6X; -. DR PDBsum; 2QCJ; -. DR PDBsum; 2QCT; -. DR PDBsum; 3BRH; -. DR PDBsum; 3H2X; -. DR PDBsum; 3OLR; -. DR PDBsum; 3OMH; -. DR PDBsum; 4J51; -. DR PDBsum; 7AAM; -. DR AlphaFoldDB; Q9Y2R2; -. DR SMR; Q9Y2R2; -. DR BioGRID; 117604; 52. DR DIP; DIP-29953N; -. DR IntAct; Q9Y2R2; 37. DR MINT; Q9Y2R2; -. DR STRING; 9606.ENSP00000352833; -. DR BindingDB; Q9Y2R2; -. DR ChEMBL; CHEMBL2889; -. DR GuidetoPHARMACOLOGY; 3084; -. DR DEPOD; PTPN22; -. DR iPTMnet; Q9Y2R2; -. DR PhosphoSitePlus; Q9Y2R2; -. DR BioMuta; PTPN22; -. DR DMDM; 20139861; -. DR jPOST; Q9Y2R2; -. DR MassIVE; Q9Y2R2; -. DR MaxQB; Q9Y2R2; -. DR PaxDb; 9606-ENSP00000352833; -. DR PeptideAtlas; Q9Y2R2; -. DR ProteomicsDB; 21761; -. DR ProteomicsDB; 22726; -. DR ProteomicsDB; 85874; -. [Q9Y2R2-1] DR ProteomicsDB; 85875; -. [Q9Y2R2-2] DR ProteomicsDB; 85876; -. [Q9Y2R2-3] DR ProteomicsDB; 85877; -. [Q9Y2R2-4] DR ProteomicsDB; 85878; -. [Q9Y2R2-5] DR Antibodypedia; 33846; 359 antibodies from 34 providers. DR DNASU; 26191; -. DR Ensembl; ENST00000460620.5; ENSP00000433141.1; ENSG00000134242.16. [Q9Y2R2-5] DR GeneID; 26191; -. DR KEGG; hsa:26191; -. DR UCSC; uc001edt.4; human. [Q9Y2R2-1] DR AGR; HGNC:9652; -. DR CTD; 26191; -. DR DisGeNET; 26191; -. DR GeneCards; PTPN22; -. DR HGNC; HGNC:9652; PTPN22. DR HPA; ENSG00000134242; Tissue enhanced (bone marrow, lymphoid tissue). DR MalaCards; PTPN22; -. DR MIM; 152700; phenotype. DR MIM; 180300; phenotype. DR MIM; 193200; phenotype. DR MIM; 222100; phenotype. DR MIM; 600716; gene. DR neXtProt; NX_Q9Y2R2; -. DR OpenTargets; ENSG00000134242; -. DR Orphanet; 397; Giant cell arteritis. DR Orphanet; 900; Granulomatosis with polyangiitis. DR Orphanet; 85410; Oligoarticular juvenile idiopathic arthritis. DR Orphanet; 85408; Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis. DR Orphanet; 536; Systemic lupus erythematosus. DR Orphanet; 3437; Vogt-Koyanagi-Harada disease. DR PharmGKB; PA33995; -. DR VEuPathDB; HostDB:ENSG00000134242; -. DR eggNOG; KOG0789; Eukaryota. DR GeneTree; ENSGT00940000160958; -. DR InParanoid; Q9Y2R2; -. DR OrthoDB; 5489271at2759; -. DR PhylomeDB; Q9Y2R2; -. DR TreeFam; TF351977; -. DR BRENDA; 3.1.3.48; 2681. DR PathwayCommons; Q9Y2R2; -. DR Reactome; R-HSA-202427; Phosphorylation of CD3 and TCR zeta chains. DR Reactome; R-HSA-202430; Translocation of ZAP-70 to Immunological synapse. DR SignaLink; Q9Y2R2; -. DR SIGNOR; Q9Y2R2; -. DR BioGRID-ORCS; 26191; 23 hits in 1184 CRISPR screens. DR ChiTaRS; PTPN22; human. DR EvolutionaryTrace; Q9Y2R2; -. DR GeneWiki; PTPN22; -. DR GenomeRNAi; 26191; -. DR Pharos; Q9Y2R2; Tchem. DR PRO; PR:Q9Y2R2; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9Y2R2; Protein. DR Bgee; ENSG00000134242; Expressed in bone marrow cell and 118 other cell types or tissues. DR ExpressionAtlas; Q9Y2R2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL. DR GO; GO:0019900; F:kinase binding; ISS:BHF-UCL. DR GO; GO:0004726; F:non-membrane spanning protein tyrosine phosphatase activity; IBA:GO_Central. DR GO; GO:0016791; F:phosphatase activity; IDA:UniProtKB. DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:UniProtKB. DR GO; GO:0017124; F:SH3 domain binding; ISS:BHF-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0071225; P:cellular response to muramyl dipeptide; IDA:UniProtKB. DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0010507; P:negative regulation of autophagy; IMP:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:UniProtKB. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:UniProtKB. DR GO; GO:0032717; P:negative regulation of interleukin-8 production; IMP:UniProtKB. DR GO; GO:0043508; P:negative regulation of JUN kinase activity; IMP:UniProtKB. DR GO; GO:0070433; P:negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IMP:UniProtKB. DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; IMP:UniProtKB. DR GO; GO:0050868; P:negative regulation of T cell activation; IMP:BHF-UCL. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:UniProtKB. DR GO; GO:0035644; P:phosphoanandamide dephosphorylation; ISS:BHF-UCL. DR GO; GO:2000566; P:positive regulation of CD8-positive, alpha-beta T cell proliferation; IBA:GO_Central. DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IBA:GO_Central. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0071663; P:positive regulation of granzyme B production; IBA:GO_Central. DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB. DR GO; GO:1902523; P:positive regulation of protein K63-linked ubiquitination; IMP:UniProtKB. DR GO; GO:0034141; P:positive regulation of toll-like receptor 3 signaling pathway; IMP:UniProtKB. DR GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; IMP:UniProtKB. DR GO; GO:0034157; P:positive regulation of toll-like receptor 7 signaling pathway; IBA:GO_Central. DR GO; GO:0034165; P:positive regulation of toll-like receptor 9 signaling pathway; IBA:GO_Central. DR GO; GO:0032481; P:positive regulation of type I interferon production; IMP:UniProtKB. DR GO; GO:0032729; P:positive regulation of type II interferon production; IMP:UniProtKB. DR GO; GO:0006470; P:protein dephosphorylation; IDA:BHF-UCL. DR GO; GO:0050855; P:regulation of B cell receptor signaling pathway; NAS:BHF-UCL. DR GO; GO:0045088; P:regulation of innate immune response; IC:BHF-UCL. DR GO; GO:0032817; P:regulation of natural killer cell proliferation; IDA:BHF-UCL. DR GO; GO:1901222; P:regulation of non-canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:UniProtKB. DR GO; GO:0030217; P:T cell differentiation; ISS:BHF-UCL. DR GO; GO:0050852; P:T cell receptor signaling pathway; IBA:GO_Central. DR CDD; cd14602; PTPc-N22; 1. DR Gene3D; 3.90.190.10; Protein tyrosine phosphatase superfamily; 1. DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like. DR InterPro; IPR047170; PTN12/18/22. DR InterPro; IPR047253; PTN22_cat. DR InterPro; IPR000242; PTP_cat. DR InterPro; IPR016276; PTPN22. DR InterPro; IPR016130; Tyr_Pase_AS. DR InterPro; IPR003595; Tyr_Pase_cat. DR InterPro; IPR000387; Tyr_Pase_dom. DR PANTHER; PTHR45983; TYROSINE PHOSPHATSE N18, PUTATIVE-RELATED; 1. DR PANTHER; PTHR45983:SF1; TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 22; 1. DR Pfam; PF00102; Y_phosphatase; 1. DR PIRSF; PIRSF000930; PTPN8_PTPN22; 1. DR PRINTS; PR00700; PRTYPHPHTASE. DR SMART; SM00194; PTPc; 1. DR SMART; SM00404; PTPc_motif; 1. DR SUPFAM; SSF52799; (Phosphotyrosine protein) phosphatases II; 1. DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1. DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1. DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1. DR Genevisible; Q9Y2R2; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Autophagy; Cytoplasm; KW Diabetes mellitus; Disease variant; Disulfide bond; Hydrolase; Immunity; KW Lipid metabolism; Phosphoprotein; Protein phosphatase; Reference proteome; KW Systemic lupus erythematosus. FT CHAIN 1..807 FT /note="Tyrosine-protein phosphatase non-receptor type 22" FT /id="PRO_0000094775" FT DOMAIN 24..289 FT /note="Tyrosine-protein phosphatase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160" FT REGION 676..700 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 724..746 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 227 FT /note="Phosphocysteine intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160, FT ECO:0000255|PROSITE-ProRule:PRU10044" FT BINDING 227..233 FT /ligand="substrate" FT /evidence="ECO:0000269|Ref.20" FT BINDING 274 FT /ligand="substrate" FT /evidence="ECO:0000269|Ref.20" FT MOD_RES 35 FT /note="Phosphoserine; by PKC/PRKCD" FT /evidence="ECO:0000269|PubMed:18056643" FT MOD_RES 449 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 635 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P29352" FT MOD_RES 684 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P29352" FT MOD_RES 692 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P29352" FT DISULFID 129..227 FT /evidence="ECO:0000269|PubMed:19371084" FT VAR_SEQ 124..250 FT /note="Missing (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044428" FT VAR_SEQ 137..160 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_039725" FT VAR_SEQ 181..203 FT /note="ETRTIYQFHYKNWPDHDVPSSID -> VSVILAHQTSLQNLFSQITPAHF FT (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_039726" FT VAR_SEQ 204..807 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_039727" FT VAR_SEQ 251..305 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_039728" FT VAR_SEQ 647..674 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:21044313" FT /id="VSP_039729" FT VAR_SEQ 685..807 FT /note="ELHQDRSSPPPPLPERTLESFFLADEDCMQAQSIETYSTSYPDTMENSTSSK FT QTLKTPGKSFTRSKSLKILRNMKKSICNSCPPNKPAESVQSNNSSSFLNFGFANRFSKP FT KGPRNPPPTWNI -> GKNFSWL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10068674" FT /id="VSP_005134" FT VAR_SEQ 788..807 FT /note="FANRFSKPKGPRNPPPTWNI -> MCVILLKS (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_044429" FT VARIANT 201 FT /note="S -> F (moderately reduces phosphatase activity; FT dbSNP:rs7416347)" FT /evidence="ECO:0000269|PubMed:22952725" FT /id="VAR_072629" FT VARIANT 263 FT /note="R -> Q (probable protective factor against SLE; FT severely reduces phosphatase activity; dbSNP:rs33996649)" FT /evidence="ECO:0000269|PubMed:18981062, FT ECO:0000269|PubMed:21287672, ECO:0000269|PubMed:22952725" FT /id="VAR_072630" FT VARIANT 266 FT /note="R -> W (severely reduces phosphatase activity; FT dbSNP:rs72650670)" FT /evidence="ECO:0000269|PubMed:22952725" FT /id="VAR_072631" FT VARIANT 620 FT /note="R -> W (risk factor for T1D; risk factor for RA; FT risk factor for SLE; risk factor for VTLG; probable FT protective factor against Crohn disease; also found in FT patients with Graves disease, Hashimoto thyroiditis and FT Addison disease; affects CSK kinase binding; alters B cell FT receptor signaling and memory B cell proliferation; FT dbSNP:rs2476601)" FT /evidence="ECO:0000269|PubMed:15004560, FT ECO:0000269|PubMed:15208781, ECO:0000269|PubMed:15273934, FT ECO:0000269|PubMed:15531553, ECO:0000269|PubMed:15719322, FT ECO:0000269|PubMed:16015369, ECO:0000269|PubMed:16710414, FT ECO:0000269|PubMed:19265110, ECO:0000269|PubMed:21044313, FT ECO:0000269|PubMed:21287672, ECO:0000269|Ref.3, FT ECO:0000269|Ref.7" FT /id="VAR_022605" FT MUTAGEN 35 FT /note="S->E: Loss of phosphorylation by PKC/PRKCD." FT /evidence="ECO:0000269|PubMed:18056643" FT MUTAGEN 36 FT /note="T->E: No effect on phosphorylation by PKC/PRKCD." FT /evidence="ECO:0000269|PubMed:18056643" FT MUTAGEN 129 FT /note="C->S: Decreases activity 2 fold." FT /evidence="ECO:0000269|PubMed:19371084" FT MUTAGEN 231 FT /note="C->S: Decreases activity 7 fold." FT /evidence="ECO:0000269|PubMed:19371084" FT CONFLICT 51..52 FT /note="KP -> NA (in Ref. 1; AAD00904/AAD00905)" FT /evidence="ECO:0000305" FT CONFLICT 126 FT /note="V -> G (in Ref. 2; AAD27764)" FT /evidence="ECO:0000305" FT CONFLICT 147 FT /note="G -> V (in Ref. 2; AAD27764)" FT /evidence="ECO:0000305" FT CONFLICT 240 FT /note="I -> IV (in Ref. 1; AAD00905)" FT /evidence="ECO:0000305" FT CONFLICT 372 FT /note="A -> V (in Ref. 4; AK310570)" FT /evidence="ECO:0000305" FT CONFLICT 420 FT /note="L -> P (in Ref. 2; AAD27764)" FT /evidence="ECO:0000305" FT CONFLICT 742 FT /note="P -> S (in Ref. 2; AAD27764)" FT /evidence="ECO:0000305" FT HELIX 3..16 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 21..40 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 47..50 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 52..55 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 59..62 FT /evidence="ECO:0007829|PDB:3OMH" FT HELIX 67..69 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 70..72 FT /evidence="ECO:0007829|PDB:4J51" FT TURN 80..83 FT /evidence="ECO:0007829|PDB:4J51" FT STRAND 86..92 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 95..102 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 107..109 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 110..119 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 124..127 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 131..133 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 135..137 FT /evidence="ECO:0007829|PDB:3BRH" FT STRAND 146..148 FT /evidence="ECO:0007829|PDB:2QCJ" FT STRAND 151..153 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 156..165 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 167..178 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 181..190 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 195..197 FT /evidence="ECO:0007829|PDB:2QCJ" FT HELIX 199..202 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 203..215 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 218..221 FT /evidence="ECO:0007829|PDB:3BRH" FT STRAND 223..226 FT /evidence="ECO:0007829|PDB:2P6X" FT STRAND 228..232 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 233..248 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 258..266 FT /evidence="ECO:0007829|PDB:2P6X" FT HELIX 276..301 FT /evidence="ECO:0007829|PDB:2P6X" SQ SEQUENCE 807 AA; 91705 MW; 1ABE8AE89C9D9FBF CRC64; MDQREILQKF LDEAQSKKIT KEEFANEFLK LKRQSTKYKA DKTYPTTVAE KPKNIKKNRY KDILPYDYSR VELSLITSDE DSSYINANFI KGVYGPKAYI ATQGPLSTTL LDFWRMIWEY SVLIIVMACM EYEMGKKKCE RYWAEPGEMQ LEFGPFSVSC EAEKRKSDYI IRTLKVKFNS ETRTIYQFHY KNWPDHDVPS SIDPILELIW DVRCYQEDDS VPICIHCSAG CGRTGVICAI DYTWMLLKDG IIPENFSVFS LIREMRTQRP SLVQTQEQYE LVYNAVLELF KRQMDVIRDK HSGTESQAKH CIPEKNHTLQ ADSYSPNLPK STTKAAKMMN QQRTKMEIKE SSSFDFRTSE ISAKEELVLH PAKSSTSFDF LELNYSFDKN ADTTMKWQTK AFPIVGEPLQ KHQSLDLGSL LFEGCSNSKP VNAAGRYFNS KVPITRTKST PFELIQQRET KEVDSKENFS YLESQPHDSC FVEMQAQKVM HVSSAELNYS LPYDSKHQIR NASNVKHHDS SALGVYSYIP LVENPYFSSW PPSGTSSKMS LDLPEKQDGT VFPSSLLPTS STSLFSYYNS HDSLSLNSPT NISSLLNQES AVLATAPRID DEIPPPLPVR TPESFIVVEE AGEFSPNVPK SLSSAVKVKI GTSLEWGGTS EPKKFDDSVI LRPSKSVKLR SPKSELHQDR SSPPPPLPER TLESFFLADE DCMQAQSIET YSTSYPDTME NSTSSKQTLK TPGKSFTRSK SLKILRNMKK SICNSCPPNK PAESVQSNNS SSFLNFGFAN RFSKPKGPRN PPPTWNI //