ID PTN2_HUMAN Reviewed; 415 AA. AC P17706; A8K955; A8MXU3; K7ENG3; Q96AU5; Q96HR2; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 05-MAY-2009, sequence version 2. DT 27-MAR-2024, entry version 228. DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 2; DE EC=3.1.3.48; DE AltName: Full=T-cell protein-tyrosine phosphatase; DE Short=TCPTP; GN Name=PTPN2; Synonyms=PTPT; 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] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=T-cell; RX PubMed=2546150; DOI=10.1073/pnas.86.14.5257; RA Cool D., Tonks N.K., Charbonneau H., Walsh K.A., Fischer E.H., Krebs E.G.; RT "cDNA isolated from a human T-cell library encodes a member of the protein- RT tyrosine-phosphatase family."; RL Proc. Natl. Acad. Sci. U.S.A. 86:5257-5261(1989). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Testis; 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 [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16177791; DOI=10.1038/nature03983; RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D., RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J., RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L., RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A., RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C., RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K., RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R., RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.; RT "DNA sequence and analysis of human chromosome 18."; RL Nature 437:551-555(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Brain, and Eye; 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 [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 350-415 (ISOFORM 2), AND TISSUE SPECIFICITY. RX PubMed=1731319; DOI=10.1073/pnas.89.2.499; RA Mosinger B. Jr., Tillmann U., Westphal H., Tremblay M.L.; RT "Cloning and characterization of a mouse cDNA encoding a cytoplasmic RT protein-tyrosine-phosphatase."; RL Proc. Natl. Acad. Sci. U.S.A. 89:499-503(1992). RN [8] RP SUBCELLULAR LOCATION (ISOFORMS 1 AND 2), AND MUTAGENESIS OF RP 350-ARG--ARG-352 AND LYS-380. RX PubMed=7593185; DOI=10.1083/jcb.131.3.631; RA Lorenzen J.A., Dadabay C.Y., Fischer E.H.; RT "COOH-terminal sequence motifs target the T cell protein tyrosine RT phosphatase to the ER and nucleus."; RL J. Cell Biol. 131:631-643(1995). RN [9] RP ACTIVITY REGULATION. RX PubMed=9361013; DOI=10.1074/jbc.272.46.29322; RA Hao L., Tiganis T., Tonks N.K., Charbonneau H.; RT "The noncatalytic C-terminal segment of the T cell protein tyrosine RT phosphatase regulates activity via an intramolecular mechanism."; RL J. Biol. Chem. 272:29322-29329(1997). RN [10] RP FUNCTION IN DEPHOSPHORYLATION OF EGFR AND SHC1, MUTAGENESIS OF ASP-182, AND RP SUBCELLULAR LOCATION (ISOFORM 2). RX PubMed=9488479; DOI=10.1128/mcb.18.3.1622; RA Tiganis T., Bennett A.M., Ravichandran K.S., Tonks N.K.; RT "Epidermal growth factor receptor and the adaptor protein p52Shc are RT specific substrates of T-cell protein tyrosine phosphatase."; RL Mol. Cell. Biol. 18:1622-1634(1998). RN [11] RP FUNCTION IN DEPHOSPHORYLATION OF INSR. RX PubMed=10734133; DOI=10.1074/jbc.275.13.9792; RA Waelchli S., Curchod M.L., Gobert R.P., Arkinstall S., RA Hooft van Huijsduijnen R.; RT "Identification of tyrosine phosphatases that dephosphorylate the insulin RT receptor. A brute force approach based on 'substrate-trapping' mutants."; RL J. Biol. Chem. 275:9792-9796(2000). RN [12] RP FUNCTION IN DEPHOSPHORYLATION OF STAT3(ISOFORM 2). RX PubMed=12359225; DOI=10.1016/s0006-291x(02)02291-x; RA Yamamoto T., Sekine Y., Kashima K., Kubota A., Sato N., Aoki N., RA Matsuda T.; RT "The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates RT interleukin-6-mediated signaling pathway through STAT3 dephosphorylation."; RL Biochem. Biophys. Res. Commun. 297:811-817(2002). RN [13] RP FUNCTION IN DEPHOSPHORYLATION OF JAK1 AND JAK3, AND INTERACTION WITH JAK1 RP AND JAK3. RX PubMed=11909529; DOI=10.1016/s0960-9822(02)00697-8; RA Simoncic P.D., Lee-Loy A., Barber D.L., Tremblay M.L., McGlade C.J.; RT "The T cell protein tyrosine phosphatase is a negative regulator of janus RT family kinases 1 and 3."; RL Curr. Biol. 12:446-453(2002). RN [14] RP FUNCTION IN DEPHOSPHORYLATION OF STAT1. RX PubMed=12138178; DOI=10.1128/mcb.22.16.5662-5668.2002; RA ten Hoeve J., de Jesus Ibarra-Sanchez M., Fu Y., Zhu W., Tremblay M., RA David M., Shuai K.; RT "Identification of a nuclear Stat1 protein tyrosine phosphatase."; RL Mol. Cell. Biol. 22:5662-5668(2002). RN [15] RP FUNCTION IN DEPHOSPHORYLATION OF INSR, MUTAGENESIS OF ASP-182, AND RP SUBCELLULAR LOCATION (ISOFORM 2). RX PubMed=12612081; DOI=10.1128/mcb.23.6.2096-2108.2003; RA Galic S., Klingler-Hoffmann M., Fodero-Tavoletti M.T., Puryer M.A., RA Meng T.C., Tonks N.K., Tiganis T.; RT "Regulation of insulin receptor signaling by the protein tyrosine RT phosphatase TCPTP."; RL Mol. Cell. Biol. 23:2096-2108(2003). RN [16] RP PHOSPHORYLATION AT SER-304 BY CDK1 AND CDK2 (ISOFORM 2), AND MUTAGENESIS OF RP SER-304. RX PubMed=15030318; DOI=10.1042/bj20031780; RA Bukczynska P., Klingler-Hoffmann M., Mitchelhill K.I., Lam M.H., RA Ciccomancini M., Tonks N.K., Sarcevic B., Kemp B.E., Tiganis T.; RT "The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by RT cyclin-dependent protein kinases in mitosis."; RL Biochem. J. 380:939-949(2004). RN [17] RP FUNCTION IN DEPHOSPHORYLATION OF PDGFRB. RX PubMed=14966296; DOI=10.1128/mcb.24.5.2190-2201.2004; RA Persson C., Saevenhed C., Bourdeau A., Tremblay M.L., Markova B., RA Boehmer F.D., Haj F.G., Neel B.G., Elson A., Heldin C.H., Roennstrand L., RA Ostman A., Hellberg C.; RT "Site-selective regulation of platelet-derived growth factor beta receptor RT tyrosine phosphorylation by T-cell protein tyrosine phosphatase."; RL Mol. Cell. Biol. 24:2190-2201(2004). RN [18] RP INTERACTION WITH RMDN3. RX PubMed=15609043; DOI=10.1007/s00418-004-0732-7; RA Stenzinger A., Kajosch T., Tag C., Porsche A., Welte I., Hofer H.W., RA Steger K., Wimmer M.; RT "The novel protein PTPIP51 exhibits tissue- and cell-specific expression."; RL Histochem. Cell Biol. 123:19-28(2005). RN [19] RP FUNCTION IN DEPHOSPHORYLATION OF EGFR, INTERACTION WITH ITGA1, AND RP SUBCELLULAR LOCATION. RX PubMed=15592458; DOI=10.1038/ncb1209; RA Mattila E., Pellinen T., Nevo J., Vuoriluoto K., Arjonen A., Ivaska J.; RT "Negative regulation of EGFR signalling through integrin-alpha1beta1- RT mediated activation of protein tyrosine phosphatase TCPTP."; RL Nat. Cell Biol. 7:78-85(2005). RN [20] RP INTERACTION WITH TRAF2. RX PubMed=15696169; DOI=10.1038/ni1169; RA van Vliet C., Bukczynska P.E., Puryer M.A., Sadek C.M., Shields B.J., RA Tremblay M.L., Tiganis T.; RT "Selective regulation of tumor necrosis factor-induced Erk signaling by Src RT family kinases and the T cell protein tyrosine phosphatase."; RL Nat. Immunol. 6:253-260(2005). RN [21] RP PHOSPHORYLATION BY PKR. RX PubMed=16431927; DOI=10.1074/jbc.m504977200; RA Wang S., Raven J.F., Baltzis D., Kazemi S., Brunet D.V., Hatzoglou M., RA Tremblay M.L., Koromilas A.E.; RT "The catalytic activity of the eukaryotic initiation factor-2alpha kinase RT PKR is required to negatively regulate Stat1 and Stat3 via activation of RT the T-cell protein-tyrosine phosphatase."; RL J. Biol. Chem. 281:9439-9449(2006). RN [22] RP INTERACTION WITH TMED9. RX PubMed=16595549; DOI=10.1242/jcs.02885; RA Gupta V., Swarup G.; RT "Evidence for a role of transmembrane protein p25 in localization of RT protein tyrosine phosphatase TC48 to the ER."; RL J. Cell Sci. 119:1703-1714(2006). RN [23] RP FUNCTION IN DEPHOSPHORYLATION OF STAT6 (ISOFORM 2), AND INDUCTION BY IL4. RX PubMed=17210636; DOI=10.1128/mcb.01234-06; RA Lu X., Chen J., Sasmono R.T., Hsi E.D., Sarosiek K.A., Tiganis T., RA Lossos I.S.; RT "T-cell protein tyrosine phosphatase, distinctively expressed in activated- RT B-cell-like diffuse large B-cell lymphomas, is the nuclear phosphatase of RT STAT6."; RL Mol. Cell. Biol. 27:2166-2179(2007). RN [24] RP FUNCTION IN DEPHOSPHORYLATION OF MET, AND INTERACTION WITH MET. RX PubMed=18819921; DOI=10.1074/jbc.m805916200; RA Sangwan V., Paliouras G.N., Abella J.V., Dube N., Monast A., Tremblay M.L., RA Park M.; RT "Regulation of the Met receptor-tyrosine kinase by the protein-tyrosine RT phosphatase 1B and T-cell phosphatase."; RL J. Biol. Chem. 283:34374-34383(2008). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-298 AND SER-304, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-304, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [27] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [28] RP FUNCTION IN DEPHOSPHORYLATION OF LCK AND FYN. RX PubMed=22080863; DOI=10.1172/jci59492; RA Wiede F., Shields B.J., Chew S.H., Kyparissoudis K., van Vliet C., RA Galic S., Tremblay M.L., Russell S.M., Godfrey D.I., Tiganis T.; RT "T cell protein tyrosine phosphatase attenuates T cell signaling to RT maintain tolerance in mice."; RL J. Clin. Invest. 121:4758-4774(2011). RN [29] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-304, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [30] RP INTERACTION WITH STX17, AND SUBCELLULAR LOCATION. RX PubMed=23006999; DOI=10.1016/j.bbamcr.2012.09.003; RA Muppirala M., Gupta V., Swarup G.; RT "Tyrosine phosphorylation of a SNARE protein, Syntaxin 17: Implications for RT membrane trafficking in the early secretory pathway."; RL Biochim. Biophys. Acta 1823:2109-2119(2012). RN [31] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-293; SER-298 AND SER-304, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and 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 [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-298 AND SER-304, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [33] RP X-RAY CRYSTALLOGRAPHY (2.56 ANGSTROMS) OF 1-314, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=11907034; DOI=10.1074/jbc.m200567200; RA Iversen L.F., Moller K.B., Pedersen A.K., Peters G.H., Petersen A.S., RA Andersen H.S., Branner S., Mortensen S.B., Moller N.P.; RT "Structure determination of T cell protein-tyrosine phosphatase."; RL J. Biol. Chem. 277:19982-19990(2002). CC -!- FUNCTION: Non-receptor type tyrosine-specific phosphatase that CC dephosphorylates receptor protein tyrosine kinases including INSR, CC EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine CC kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and CC STAT6 either in the nucleus or the cytoplasm. Negatively regulates CC numerous signaling pathways and biological processes like CC hematopoiesis, inflammatory response, cell proliferation and CC differentiation, and glucose homeostasis. Plays a multifaceted and CC important role in the development of the immune system. Functions in T- CC cell receptor signaling through dephosphorylation of FYN and LCK to CC control T-cells differentiation and activation. Dephosphorylates CSF1R, CC negatively regulating its downstream signaling and macrophage CC differentiation. Negatively regulates cytokine (IL2/interleukin-2 and CC interferon)-mediated signaling through dephosphorylation of the CC cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that CC propagate signaling downstream of the cytokine receptors. Also CC regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine CC signaling through dephosphorylation of STAT3 and STAT6 respectively. In CC addition to the immune system, it is involved in anchorage-dependent, CC negative regulation of EGF-stimulated cell growth. Activated by the CC integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates CC EGF signaling. Dephosphorylates PDGFRB and negatively regulates CC platelet-derived growth factor receptor-beta signaling pathway and CC therefore cell proliferation. Negatively regulates tumor necrosis CC factor-mediated signaling downstream via MAPK through SRC CC dephosphorylation. May also regulate the hepatocyte growth factor CC receptor signaling pathway through dephosphorylation of the hepatocyte CC growth factor receptor MET. Also plays an important role in glucose CC homeostasis. For instance, negatively regulates the insulin receptor CC signaling pathway through the dephosphorylation of INSR and control CC gluconeogenesis and liver glucose production through negative CC regulation of the IL6 signaling pathways. May also bind DNA. CC {ECO:0000269|PubMed:10734133, ECO:0000269|PubMed:11909529, CC ECO:0000269|PubMed:12138178, ECO:0000269|PubMed:12612081, CC ECO:0000269|PubMed:14966296, ECO:0000269|PubMed:15592458, CC ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:22080863, CC ECO:0000269|PubMed:9488479}. 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}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.48 mM for p-nitrophenyl phosphate (at pH 6.5 and 25 degrees CC Celsius) {ECO:0000269|PubMed:11907034}; CC -!- SUBUNIT: Interacts with RMDN3. Isoform 1 interacts with TMED9. Isoform CC 1 interacts with STX17; dephosphorylates STX17. Interacts with ITGA1 CC (via cytoplasmic domain); activates the phosphatase activity towards CC EGFR. Interacts with TRAF2; probably involved in tumor necrosis factor- CC mediated signaling. Interacts with MET. {ECO:0000269|PubMed:11909529, CC ECO:0000269|PubMed:15592458, ECO:0000269|PubMed:15609043, CC ECO:0000269|PubMed:15696169, ECO:0000269|PubMed:16595549, CC ECO:0000269|PubMed:18819921, ECO:0000269|PubMed:23006999}. CC -!- INTERACTION: CC P17706; P10912: GHR; NbExp=8; IntAct=EBI-984930, EBI-286316; CC P17706; Q2GHU2: ECH_0166; Xeno; NbExp=4; IntAct=EBI-984930, EBI-26585631; CC P17706-1; P49755: TMED10; NbExp=5; IntAct=EBI-4409481, EBI-998422; CC P17706-1; Q9BVK6: TMED9; NbExp=5; IntAct=EBI-4409481, EBI-1056827; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum CC {ECO:0000269|PubMed:7593185}. Endoplasmic reticulum-Golgi intermediate CC compartment {ECO:0000269|PubMed:7593185}. Note=Targeted to the CC endoplasmic reticulum by its C-terminal hydrophobic region. CC {ECO:0000269|PubMed:7593185}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus. Cytoplasm. Cell membrane. CC Note=Predominantly localizes to chromatin (By similarity). Able to CC shuttle between the nucleus and the cytoplasm and to dephosphorylate CC plasma membrane receptors (PubMed:9488479). Recruited by activated CC ITGA1 at the plasma membrane. {ECO:0000250, CC ECO:0000269|PubMed:9488479}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=PTPB, p48TC, TC48, TC-PTPb; CC IsoId=P17706-1; Sequence=Displayed; CC Name=2; Synonyms=PTPA, p45TC, TC45, TC-PTPa; CC IsoId=P17706-2; Sequence=VSP_005125; CC Name=3; CC IsoId=P17706-3; Sequence=VSP_043383, VSP_005125; CC Name=4; CC IsoId=P17706-4; Sequence=VSP_054821, VSP_005125; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Isoform 2 is probably the CC major isoform. Isoform 1 is expressed in T-cells and in placenta. CC {ECO:0000269|PubMed:1731319, ECO:0000269|PubMed:2546150}. CC -!- INDUCTION: Up-regulated by IL4/interleukin-4 (at protein level). CC {ECO:0000269|PubMed:17210636}. CC -!- PTM: [Isoform 2]: Specifically phosphorylated in a cell cycle-dependent CC manner by cyclin-dependent kinases CDK1 and CDK2. Probably activated CC through phosphorylation by PKR. {ECO:0000269|PubMed:15030318, CC ECO:0000269|PubMed:16431927}. CC -!- MISCELLANEOUS: [Isoform 1]: Minor isoform. CC -!- MISCELLANEOUS: [Isoform 2]: Major isoform. Contains a nuclear location CC signal at positions 377-381 (PubMed:7593185) and an autoinhibitory CC region acting through intramolecular interactions is found at positions CC 353-387. {ECO:0000269|PubMed:15030318, ECO:0000305|PubMed:7593185}. CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family. Non- CC receptor class 1 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; M25393; AAA65997.1; -; mRNA. DR EMBL; AK292570; BAF85259.1; -; mRNA. DR EMBL; EF445017; ACA06062.1; -; Genomic_DNA. DR EMBL; EF445017; ACA06064.1; -; Genomic_DNA. DR EMBL; AP001077; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP002449; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP005482; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471113; EAX01532.1; -; Genomic_DNA. DR EMBL; CH471113; EAX01539.1; -; Genomic_DNA. DR EMBL; BC008244; AAH08244.1; -; mRNA. DR EMBL; BC016727; AAH16727.1; -; mRNA. DR EMBL; M81478; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS11863.1; -. [P17706-2] DR CCDS; CCDS11864.1; -. [P17706-3] DR CCDS; CCDS11865.1; -. [P17706-1] DR CCDS; CCDS59306.1; -. [P17706-4] DR PIR; A33899; A33899. DR RefSeq; NP_001193942.1; NM_001207013.1. [P17706-4] DR RefSeq; NP_002819.2; NM_002828.3. [P17706-1] DR RefSeq; NP_536347.1; NM_080422.2. [P17706-2] DR RefSeq; NP_536348.1; NM_080423.2. [P17706-3] DR PDB; 1L8K; X-ray; 2.56 A; A=1-314. DR PDB; 6ZZ4; X-ray; 2.43 A; A/B=1-314. DR PDB; 7F5N; X-ray; 1.93 A; A/B/C=1-314. DR PDB; 7F5O; X-ray; 1.70 A; A/B/C=1-302. DR PDB; 7UAD; X-ray; 2.04 A; A=1-314. DR PDBsum; 1L8K; -. DR PDBsum; 6ZZ4; -. DR PDBsum; 7F5N; -. DR PDBsum; 7F5O; -. DR PDBsum; 7UAD; -. DR AlphaFoldDB; P17706; -. DR SMR; P17706; -. DR BioGRID; 111737; 200. DR CORUM; P17706; -. DR IntAct; P17706; 59. DR MINT; P17706; -. DR STRING; 9606.ENSP00000311857; -. DR BindingDB; P17706; -. DR ChEMBL; CHEMBL3807; -. DR TCDB; 8.A.128.1.13; the signaling adaptor protein karap/dap12/tyrobp (sap) family. DR DEPOD; PTPN2; -. DR GlyCosmos; P17706; 1 site, 1 glycan. DR GlyGen; P17706; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P17706; -. DR MetOSite; P17706; -. DR PhosphoSitePlus; P17706; -. DR BioMuta; PTPN2; -. DR DMDM; 229462762; -. DR EPD; P17706; -. DR jPOST; P17706; -. DR MassIVE; P17706; -. DR MaxQB; P17706; -. DR PaxDb; 9606-ENSP00000311857; -. DR PeptideAtlas; P17706; -. DR ProteomicsDB; 53507; -. [P17706-1] DR ProteomicsDB; 53508; -. [P17706-2] DR ProteomicsDB; 53509; -. [P17706-3] DR Pumba; P17706; -. DR Antibodypedia; 6936; 335 antibodies from 34 providers. DR CPTC; P17706; 1 antibody. DR DNASU; 5771; -. DR Ensembl; ENST00000309660.10; ENSP00000311857.3; ENSG00000175354.20. [P17706-1] DR Ensembl; ENST00000327283.7; ENSP00000320298.3; ENSG00000175354.20. [P17706-2] DR Ensembl; ENST00000353319.8; ENSP00000320546.3; ENSG00000175354.20. [P17706-3] DR Ensembl; ENST00000591115.5; ENSP00000466936.1; ENSG00000175354.20. [P17706-4] DR GeneID; 5771; -. DR KEGG; hsa:5771; -. DR MANE-Select; ENST00000309660.10; ENSP00000311857.3; NM_002828.4; NP_002819.2. DR UCSC; uc002krl.4; human. [P17706-1] DR AGR; HGNC:9650; -. DR CTD; 5771; -. DR DisGeNET; 5771; -. DR GeneCards; PTPN2; -. DR HGNC; HGNC:9650; PTPN2. DR HPA; ENSG00000175354; Tissue enhanced (lymphoid). DR MalaCards; PTPN2; -. DR MIM; 176887; gene. DR neXtProt; NX_P17706; -. DR OpenTargets; ENSG00000175354; -. DR Orphanet; 206; NON RARE IN EUROPE: Crohn disease. DR Orphanet; 771; NON RARE IN EUROPE: Ulcerative colitis. DR Orphanet; 85410; Oligoarticular juvenile idiopathic arthritis. DR Orphanet; 85408; Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis. DR PharmGKB; PA33993; -. DR VEuPathDB; HostDB:ENSG00000175354; -. DR eggNOG; KOG0789; Eukaryota. DR GeneTree; ENSGT00940000154686; -. DR HOGENOM; CLU_001645_9_0_1; -. DR InParanoid; P17706; -. DR OMA; NTAQMVQ; -. DR OrthoDB; 2911650at2759; -. DR PhylomeDB; P17706; -. DR TreeFam; TF315897; -. DR BRENDA; 3.1.3.48; 2681. DR PathwayCommons; P17706; -. DR Reactome; R-HSA-6807004; Negative regulation of MET activity. DR Reactome; R-HSA-877312; Regulation of IFNG signaling. [P17706-2] DR Reactome; R-HSA-9008059; Interleukin-37 signaling. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SABIO-RK; P17706; -. DR SignaLink; P17706; -. DR SIGNOR; P17706; -. DR BioGRID-ORCS; 5771; 29 hits in 1179 CRISPR screens. DR ChiTaRS; PTPN2; human. DR EvolutionaryTrace; P17706; -. DR GeneWiki; PTPN2; -. DR GenomeRNAi; 5771; -. DR Pharos; P17706; Tchem. DR PRO; PR:P17706; -. DR Proteomes; UP000005640; Chromosome 18. DR RNAct; P17706; Protein. DR Bgee; ENSG00000175354; Expressed in tendon of biceps brachii and 207 other cell types or tissues. DR ExpressionAtlas; P17706; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; IDA:UniProtKB. DR GO; GO:0031904; C:endosome lumen; IEA:Ensembl. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005178; F:integrin binding; IPI:UniProtKB. DR GO; GO:0004726; F:non-membrane spanning protein tyrosine phosphatase activity; IBA:GO_Central. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; IPI:UniProtKB. DR GO; GO:0097677; F:STAT family protein binding; IEA:Ensembl. DR GO; GO:0019905; F:syntaxin binding; IPI:UniProtKB. DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB. DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0038020; P:insulin receptor recycling; IEA:Ensembl. DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:UniProtKB. DR GO; GO:0050922; P:negative regulation of chemotaxis; ISS:UniProtKB. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:1902206; P:negative regulation of interleukin-2-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:1902215; P:negative regulation of interleukin-4-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0070104; P:negative regulation of interleukin-6-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0010888; P:negative regulation of lipid storage; ISS:UniProtKB. DR GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; ISS:UniProtKB. DR GO; GO:0045650; P:negative regulation of macrophage differentiation; ISS:UniProtKB. DR GO; GO:2000587; P:negative regulation of platelet-derived growth factor receptor-beta signaling pathway; ISS:UniProtKB. DR GO; GO:1902233; P:negative regulation of positive thymic T cell selection; ISS:UniProtKB. DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IBA:GO_Central. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; IMP:UniProtKB. DR GO; GO:0060336; P:negative regulation of type II interferon-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; IDA:UniProtKB. DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; IMP:UniProtKB. DR GO; GO:1902237; P:positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; IEA:Ensembl. DR GO; GO:0045722; P:positive regulation of gluconeogenesis; ISS:UniProtKB. DR GO; GO:1903899; P:positive regulation of PERK-mediated unfolded protein response; IEA:Ensembl. DR GO; GO:1902202; P:regulation of hepatocyte growth factor receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0060334; P:regulation of type II interferon-mediated signaling pathway; TAS:Reactome. DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB. DR CDD; cd14607; PTPc-N2; 1. DR Gene3D; 3.90.190.10; Protein tyrosine phosphatase superfamily; 1. DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like. DR InterPro; IPR000242; PTP_cat. DR InterPro; IPR012265; Ptpn1/Ptpn2. DR InterPro; IPR016130; Tyr_Pase_AS. DR InterPro; IPR003595; Tyr_Pase_cat. DR InterPro; IPR000387; Tyr_Pase_dom. DR PANTHER; PTHR46047:SF1; TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 2; 1. DR PANTHER; PTHR46047; TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 61F; 1. DR Pfam; PF00102; Y_phosphatase; 1. DR PIRSF; PIRSF000926; Tyr-Ptase_nr1; 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; P17706; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasm; KW Endoplasmic reticulum; Hydrolase; Membrane; Nucleus; Phosphoprotein; KW Protein phosphatase; Reference proteome; S-nitrosylation. FT CHAIN 1..415 FT /note="Tyrosine-protein phosphatase non-receptor type 2" FT /id="PRO_0000094752" FT DOMAIN 5..275 FT /note="Tyrosine-protein phosphatase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160" FT REGION 346..415 FT /note="Endoplasmic reticulum location" FT REGION 376..415 FT /note="Mediates interaction with STX17" FT /evidence="ECO:0000269|PubMed:23006999" FT ACT_SITE 216 FT /note="Phosphocysteine intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160, FT ECO:0000255|PROSITE-ProRule:PRU10044" FT BINDING 182 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 216..222 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 260 FT /ligand="substrate" FT /evidence="ECO:0000250" FT MOD_RES 22 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 52 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 68 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 216 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 293 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 298 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT MOD_RES 304 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569" FT VAR_SEQ 165 FT /note="N -> NYIENLWITLYLKLLMLDVKRSLK (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_054821" FT VAR_SEQ 347..380 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_043383" FT VAR_SEQ 382..415 FT /note="WLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL -> PRLTDT (in FT isoform 2, isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:1731319" FT /id="VSP_005125" FT MUTAGEN 182 FT /note="D->A: Substrate-trapping mutant; catalytically FT inactive it forms a stable complex with physiological FT substrates including INSR and EGFR. Accumulates in the FT cytoplasm upon stimulation by insulin or EGF; isoform 2." FT /evidence="ECO:0000269|PubMed:12612081, FT ECO:0000269|PubMed:9488479" FT MUTAGEN 222 FT /note="R->M: Impairs phosphatase activity." FT MUTAGEN 304 FT /note="S->A: Alters phosphorylation by cyclin-dependent FT kinases of isoform 2 but has no effect on its phosphatase FT activity." FT /evidence="ECO:0000269|PubMed:15030318" FT MUTAGEN 350..352 FT /note="RKR->QQQ: Alters location to the endoplasmic FT reticulum; isoform 1." FT /evidence="ECO:0000269|PubMed:7593185" FT MUTAGEN 380 FT /note="K->Q: Prevents location to the nucleus; isoform 2." FT /evidence="ECO:0000269|PubMed:7593185" FT CONFLICT 407 FT /note="T -> R (in Ref. 1; AAA65997 and 7; M81478)" FT /evidence="ECO:0000305" FT HELIX 4..14 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 18..28 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 35..38 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 40..45 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 55..57 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 58..60 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 68..76 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 77..79 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 81..86 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 91..93 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 94..104 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 108..111 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 115..117 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 129..132 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 134..136 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 137..140 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 141..150 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 152..163 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 164..166 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 169..177 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 182..184 FT /evidence="ECO:0007829|PDB:1L8K" FT HELIX 189..200 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 201..205 FT /evidence="ECO:0007829|PDB:7F5O" FT STRAND 212..221 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 222..235 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 236..238 FT /evidence="ECO:0007829|PDB:7UAD" FT HELIX 244..252 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 262..275 FT /evidence="ECO:0007829|PDB:7F5O" FT HELIX 286..293 FT /evidence="ECO:0007829|PDB:7F5O" FT TURN 294..296 FT /evidence="ECO:0007829|PDB:7F5N" FT MOD_RES P17706-2:304 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:15030318, FT ECO:0000305|PubMed:7593185" SQ SEQUENCE 415 AA; 48473 MW; 0207694A4F058E68 CRC64; MPTTIEREFE ELDTQRRWQP LYLEIRNESH DYPHRVAKFP ENRNRNRYRD VSPYDHSRVK LQNAENDYIN ASLVDIEEAQ RSYILTQGPL PNTCCHFWLM VWQQKTKAVV MLNRIVEKES VKCAQYWPTD DQEMLFKETG FSVKLLSEDV KSYYTVHLLQ LENINSGETR TISHFHYTTW PDFGVPESPA SFLNFLFKVR ESGSLNPDHG PAVIHCSAGI GRSGTFSLVD TCLVLMEKGD DINIKQVLLN MRKYRMGLIQ TPDQLRFSYM AIIEGAKCIK GDSSIQKRWK ELSKEDLSPA FDHSPNKIMT EKYNGNRIGL EEEKLTGDRC TGLSSKMQDT MEENSESALR KRIREDRKAT TAQKVQQMKQ RLNENERKRK RWLYWQPILT KMGFMSVILV GAFVGWTLFF QQNAL //