ID ITK_HUMAN Reviewed; 620 AA. AC Q08881; B2R752; Q32ML7; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1994, sequence version 1. DT 16-OCT-2013, entry version 151. DE RecName: Full=Tyrosine-protein kinase ITK/TSK; DE EC=2.7.10.2; DE AltName: Full=Interleukin-2-inducible T-cell kinase; DE Short=IL-2-inducible T-cell kinase; DE AltName: Full=Kinase EMT; DE AltName: Full=T-cell-specific kinase; DE AltName: Full=Tyrosine-protein kinase Lyk; GN Name=ITK; Synonyms=EMT, LYK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION. RX PubMed=8504851; DOI=10.1016/0014-5793(93)81520-A; RA Tanaka N., Asao H., Ohtani K., Nakamura M., Sugamura K.; RT "A novel human tyrosine kinase gene inducible in T cells by RT interleukin 2."; RL FEBS Lett. 324:1-5(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Thymus; RX PubMed=8364206; RA Gibson S., Leung B., Squire J.A., Hill M., Arima N., Goss P., Hogg D., RA Mills G.B.; RT "Identification, cloning, and characterization of a novel human T- RT cell-specific tyrosine kinase located at the hematopoietin complex on RT chromosome 5q."; RL Blood 82:1561-1572(1993). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Thymus; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP PROTEIN SEQUENCE OF 171-192, AND PHOSPHORYLATION AT TYR-180. RX PubMed=12573241; DOI=10.1016/S1570-9639(02)00524-1; RA Nore B.F., Mattsson P.T., Antonsson P., Backesjo C.-M., Westlund A., RA Lennartsson J., Hansson H., Low P., Ronnstrand L., Smith C.I.E.; RT "Identification of phosphorylation sites within the SH3 domains of Tec RT family tyrosine kinases."; RL Biochim. Biophys. Acta 1645:123-132(2003). RN [7] RP PHOSPHORYLATION BY LCK. RX PubMed=9312162; DOI=10.1074/jbc.272.40.25401; RA Heyeck S.D., Wilcox H.M., Bunnell S.C., Berg L.J.; RT "Lck phosphorylates the activation loop tyrosine of the Itk kinase RT domain and activates Itk kinase activity."; RL J. Biol. Chem. 272:25401-25408(1997). RN [8] RP INDUCTION. RX PubMed=9701039; DOI=10.1093/intimm/10.7.1009; RA King P.D., Sadra A., Teng J.M., Bell G.M., Dupont B.; RT "CD2-mediated activation of the Tec-family tyrosine kinase ITK is RT controlled by proline-rich stretch-4 of the CD2 cytoplasmic tail."; RL Int. Immunol. 10:1009-1016(1998). RN [9] RP DOMAIN. RX PubMed=10795735; DOI=10.1016/S1074-7613(00)80189-2; RA Yang W.C., Collette Y., Nunes J.A., Olive D.; RT "Tec kinases: a family with multiple roles in immunity."; RL Immunity 12:373-382(2000). RN [10] RP FUNCTION IN PHOSPHORYLATION OF LAT. RX PubMed=12186560; DOI=10.1021/bi025554o; RA Perez-Villar J.J., Whitney G.S., Sitnick M.T., Dunn R.J., RA Venkatesan S., O'Day K., Schieven G.L., Lin T.A., Kanner S.B.; RT "Phosphorylation of the linker for activation of T-cells by Itk RT promotes recruitment of Vav."; RL Biochemistry 41:10732-10740(2002). RN [11] RP FUNCTION. RX PubMed=12682224; RA Grasis J.A., Browne C.D., Tsoukas C.D.; RT "Inducible T cell tyrosine kinase regulates actin-dependent RT cytoskeletal events induced by the T cell antigen receptor."; RL J. Immunol. 170:3971-3976(2003). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites RT from human T cells using immobilized metal affinity chromatography and RT tandem mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [13] RP INTERACTION WITH PPIA/CYPA, AND MUTAGENESIS OF PRO-288. RX PubMed=15308100; DOI=10.1016/j.immuni.2004.07.005; RA Colgan J., Asmal M., Neagu M., Yu B., Schneidkraut J., Lee Y., RA Sokolskaja E., Andreotti A., Luban J.; RT "Cyclophilin A regulates TCR signal strength in CD4+ T cells via a RT proline-directed conformational switch in Itk."; RL Immunity 21:189-201(2004). RN [14] RP INTERACTION WITH VAV1. RX PubMed=15661896; RA Dombroski D., Houghtling R.A., Labno C.M., Precht P., Takesono A., RA Caplen N.J., Billadeau D.D., Wange R.L., Burkhardt J.K., RA Schwartzberg P.L.; RT "Kinase-independent functions for Itk in TCR-induced regulation of Vav RT and the actin cytoskeleton."; RL J. Immunol. 174:1385-1392(2005). RN [15] RP SUBCELLULAR LOCATION. RX PubMed=17060314; DOI=10.1074/jbc.M609180200; RA Qi Q., Sahu N., August A.; RT "Tec kinase Itk forms membrane clusters specifically in the vicinity RT of recruiting receptors."; RL J. Biol. Chem. 281:38529-38534(2006). RN [16] RP INTERACTION WITH FASLG. RX PubMed=19807924; DOI=10.1186/1471-2172-10-53; RA Voss M., Lettau M., Janssen O.; RT "Identification of SH3 domain interaction partners of human FasL RT (CD178) by phage display screening."; RL BMC Immunol. 10:53-53(2009). RN [17] RP AUTOPHOSPHORYLATION. RX PubMed=19523959; DOI=10.1016/j.jmb.2009.06.023; RA Joseph R.E., Severin A., Min L., Fulton D.B., Andreotti A.H.; RT "SH2-dependent autophosphorylation within the Tec family kinase Itk."; RL J. Mol. Biol. 391:164-177(2009). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-512 AND SER-565, AND RP MASS SPECTROMETRY. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [19] RP FUNCTION IN PHOSPHORYLATION OF LCP2. RX PubMed=21725281; DOI=10.1038/emboj.2011.213; RA Sela M., Bogin Y., Beach D., Oellerich T., Lehne J., RA Smith-Garvin J.E., Okumura M., Starosvetsky E., Kosoff R., Libman E., RA Koretzky G., Kambayashi T., Urlaub H., Wienands J., Chernoff J., RA Yablonski D.; RT "Sequential phosphorylation of SLP-76 at tyrosine 173 is required for RT activation of T and mast cells."; RL EMBO J. 30:3160-3172(2011). RN [20] RP STRUCTURE BY NMR OF 113-239. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of the BTK motif and the SH3 domain of tyrosine- RT protein kinase ITK from human."; RL Submitted (OCT-2007) to the PDB data bank. RN [21] RP VARIANTS [LARGE SCALE ANALYSIS] LYS-19; LEU-23; GLN-451; TRP-581 AND RP ILE-587. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [22] RP VARIANT LPFS1 TRP-335, AND CHARACTERIZATION OF VARIANT LPSA1 TRP-335. RX PubMed=19425169; DOI=10.1172/JCI37901; RA Huck K., Feyen O., Niehues T., Rueschendorf F., Huebner N., RA Laws H.-J., Telieps T., Knapp S., Wacker H.-H., Meindl A., Jumaa H., RA Borkhardt A.; RT "Girls homozygous for an IL-2-inducible T cell kinase mutation that RT leads to protein deficiency develop fatal EBV-associated RT lymphoproliferation."; RL J. Clin. Invest. 119:1350-1358(2009). CC -!- FUNCTION: Tyrosine kinase that plays an essential role in CC regulation of the adaptive immune response. Regulates the CC development, function and differentiation of conventional T-cells CC and nonconventional NKT-cells. When antigen presenting cells (APC) CC activate T-cell receptor (TCR), a series of phosphorylation lead CC to the recruitment of ITK to the cell membrane, in the vicinity of CC the stimulated TCR receptor, where it is phosphorylated by LCK. CC Phosphorylation leads to ITK autophosphorylation and full CC activation. Once activated, phosphorylates PLCG1, leading to the CC activation of this lipase and subsequent cleavage of its CC substrates. In turn, the endoplasmic reticulum releases calcium in CC the cytoplasm and the nuclear activator of activated T-cells CC (NFAT) translocates into the nucleus to perform its CC transcriptional duty. Phosphorylates 2 essential adapter proteins: CC the linker for activation of T-cells/LAT protein and LCP2. Then, a CC large number of signaling molecules such as VAV1 are recruited and CC ultimately lead to lymphokine production, T-cell proliferation and CC differentiation. CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. CC -!- COFACTOR: Binds 1 zinc ion per subunit (By similarity). CC -!- SUBUNIT: Homooligomerizes; this association negatively regulates CC kinase activity (By similarity). Interacts with PPIA/CYPA; this CC interaction regulates TCR signal strength via a proline-directed CC conformational switch in ITK. Interacts with THEMIS (By CC similarity). Interacts with FASLG. Interacts with VAV1; this CC interaction is important for VAV1 localization and TCR-induced CC actin polarization. CC -!- INTERACTION: CC P04626:ERBB2; NbExp=2; IntAct=EBI-968552, EBI-641062; CC P48023:FASLG; NbExp=3; IntAct=EBI-968552, EBI-495538; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Localizes in the vicinity of CC cell surface receptors in the plasma membrane after receptor CC stimulation. CC -!- TISSUE SPECIFICITY: T-cell lines and natural killer cell lines. CC -!- INDUCTION: Through a myriad of surface receptors including the CC TCR/CD3 signaling complex, coreceptors, or chemokine receptors. CC -!- DOMAIN: The N-terminal PH domain allows ITK to be recruited to the CC plasma membrane by an activated PI3 kinase. This domain contains CC also a proline-rich region (PRR). The adjoining domain is a SH3 CC domain, which binds to PRR (from itself or from other proteins). CC Next, a SH2 domain is required for binding tyrosine-phosphorylated CC substrates. In the C-terminal region, the kinase domain is CC required for tyrosine phosphorylation. CC -!- PTM: Phosphorylated at Tyr-512 in the activation loop of the CC kinase domain by LCK. Subsequent autophosphorylation at Tyr-180 CC leads to the kinase activation. The autophosphorylated Tyr-180 CC lies within the substrate binding sequence of the SH3 domain. CC -!- DISEASE: Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A CC rare immunodeficiency characterized by extreme susceptibility to CC infection with Epstein-Barr virus (EBV). Inadequate immune CC response to EBV can have a fatal outcome. Clinical features CC include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, CC pancytopenia, recurrent infections. There is an increased risk for CC lymphoma. Note=The disease is caused by mutations affecting the CC gene represented in this entry. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. TEC subfamily. CC -!- SIMILARITY: Contains 1 Btk-type zinc finger. CC -!- SIMILARITY: Contains 1 PH domain. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC -!- SIMILARITY: Contains 1 SH2 domain. CC -!- SIMILARITY: Contains 1 SH3 domain. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/ITKID43329ch5q33.html"; 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; D13720; BAA02873.1; -; mRNA. DR EMBL; L10717; AAA36748.1; -; mRNA. DR EMBL; S65186; AAB28072.2; -; mRNA. DR EMBL; AK312846; BAG35699.1; -; mRNA. DR EMBL; CH471062; EAW61608.1; -; Genomic_DNA. DR EMBL; BC109077; AAI09078.1; -; mRNA. DR EMBL; BC109078; AAI09079.1; -; mRNA. DR IPI; IPI00004566; -. DR PIR; S33253; S33253. DR RefSeq; NP_005537.3; NM_005546.3. DR UniGene; Hs.558348; -. DR PDB; 1SM2; X-ray; 2.30 A; A/B=357-620. DR PDB; 1SNU; X-ray; 2.50 A; A/B=357-620. DR PDB; 1SNX; X-ray; 3.20 A; A/B=357-620. DR PDB; 2E6I; NMR; -; A=113-169. DR PDB; 2LMJ; NMR; -; A=171-231. DR PDB; 2YUQ; NMR; -; A=162-239. DR PDB; 3MIY; X-ray; 1.67 A; A/B=357-620. DR PDB; 3MJ1; X-ray; 1.72 A; A=357-620. DR PDB; 3MJ2; X-ray; 1.90 A; A=357-620. DR PDB; 3QGW; X-ray; 2.10 A; A/B=357-620. DR PDB; 3QGY; X-ray; 2.10 A; A/B=357-620. DR PDB; 3T9T; X-ray; 1.65 A; A=354-620. DR PDB; 3V5J; X-ray; 2.59 A; A/B=357-620. DR PDB; 3V5L; X-ray; 1.86 A; A/B/C/D=357-620. DR PDB; 3V8T; X-ray; 2.00 A; A/B=357-620. DR PDB; 3V8W; X-ray; 2.27 A; A/B=357-620. DR PDB; 4HCT; X-ray; 1.48 A; A=354-620. DR PDB; 4HCU; X-ray; 1.43 A; A=354-620. DR PDB; 4HCV; X-ray; 1.48 A; A=354-620. DR PDBsum; 1SM2; -. DR PDBsum; 1SNU; -. DR PDBsum; 1SNX; -. DR PDBsum; 2E6I; -. DR PDBsum; 2LMJ; -. DR PDBsum; 2YUQ; -. DR PDBsum; 3MIY; -. DR PDBsum; 3MJ1; -. DR PDBsum; 3MJ2; -. DR PDBsum; 3QGW; -. DR PDBsum; 3QGY; -. DR PDBsum; 3T9T; -. DR PDBsum; 3V5J; -. DR PDBsum; 3V5L; -. DR PDBsum; 3V8T; -. DR PDBsum; 3V8W; -. DR PDBsum; 4HCT; -. DR PDBsum; 4HCU; -. DR PDBsum; 4HCV; -. DR ProteinModelPortal; Q08881; -. DR SMR; Q08881; 1-618. DR DIP; DIP-29974N; -. DR IntAct; Q08881; 8. DR MINT; MINT-110502; -. DR STRING; 9606.ENSP00000398655; -. DR PhosphoSite; Q08881; -. DR DMDM; 585361; -. DR PaxDb; Q08881; -. DR PeptideAtlas; Q08881; -. DR PRIDE; Q08881; -. DR DNASU; 3702; -. DR Ensembl; ENST00000422843; ENSP00000398655; ENSG00000113263. DR GeneID; 3702; -. DR KEGG; hsa:3702; -. DR UCSC; uc003lwo.1; human. DR CTD; 3702; -. DR GeneCards; GC05P156607; -. DR HGNC; HGNC:6171; ITK. DR MIM; 186973; gene. DR MIM; 613011; phenotype. DR neXtProt; NX_Q08881; -. DR Orphanet; 238505; Autosomal recessive lymphoproliferative disease. DR PharmGKB; PA29968; -. DR eggNOG; COG0515; -. DR HOGENOM; HOG000233859; -. DR HOVERGEN; HBG008761; -. DR InParanoid; Q08881; -. DR KO; K07363; -. DR OMA; RRNEEYC; -. DR OrthoDB; EOG48WC1S; -. DR BRENDA; 2.7.10.2; 2681. DR Reactome; REACT_6900; Immune System. DR SignaLink; Q08881; -. DR BindingDB; Q08881; -. DR ChEMBL; CHEMBL2959; -. DR EvolutionaryTrace; Q08881; -. DR GeneWiki; ITK_(gene); -. DR GenomeRNAi; 3702; -. DR NextBio; 14507; -. DR PRO; PR:Q08881; -. DR ArrayExpress; Q08881; -. DR Bgee; Q08881; -. DR CleanEx; HS_ITK; -. DR Genevestigator; Q08881; -. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro. DR GO; GO:0007202; P:activation of phospholipase C activity; ISS:UniProtKB. DR GO; GO:0002250; P:adaptive immune response; ISS:UniProtKB. DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc. DR GO; GO:0001816; P:cytokine production; ISS:UniProtKB. DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome. DR GO; GO:0045087; P:innate immune response; TAS:Reactome. DR GO; GO:0032609; P:interferon-gamma production; IEA:Ensembl. DR GO; GO:0032633; P:interleukin-4 production; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:0001865; P:NK T cell differentiation; IEA:Ensembl. DR GO; GO:0042110; P:T cell activation; TAS:UniProtKB. DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB. DR Gene3D; 2.30.29.30; -; 1. DR Gene3D; 3.30.505.10; -; 1. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR011993; PH_like_dom. DR InterPro; IPR001849; Pleckstrin_homology. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR001452; SH3_domain. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR001562; Znf_Btk_motif. DR Pfam; PF00779; BTK; 1. DR Pfam; PF00169; PH; 1. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF00017; SH2; 1. DR Pfam; PF00018; SH3_1; 1. DR PRINTS; PR00401; SH2DOMAIN. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00107; BTK; 1. DR SMART; SM00233; PH; 1. DR SMART; SM00252; SH2; 1. DR SMART; SM00326; SH3; 1. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF50044; SSF50044; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; PS50001; SH2; 1. DR PROSITE; PS50002; SH3; 1. DR PROSITE; PS51113; ZF_BTK; 1. PE 1: Evidence at protein level; KW 3D-structure; Adaptive immunity; ATP-binding; Complete proteome; KW Cytoplasm; Direct protein sequencing; Disease mutation; Immunity; KW Kinase; Metal-binding; Nucleotide-binding; Phosphoprotein; KW Polymorphism; Reference proteome; SH2 domain; SH3 domain; Transferase; KW Tyrosine-protein kinase; Zinc; Zinc-finger. FT CHAIN 1 620 Tyrosine-protein kinase ITK/TSK. FT /FTId=PRO_0000088106. FT DOMAIN 4 111 PH. FT DOMAIN 171 231 SH3. FT DOMAIN 239 338 SH2. FT DOMAIN 363 615 Protein kinase. FT ZN_FING 113 149 Btk-type. FT NP_BIND 369 377 ATP (By similarity). FT ACT_SITE 482 482 Proton acceptor (By similarity). FT METAL 121 121 Zinc (By similarity). FT METAL 132 132 Zinc (By similarity). FT METAL 133 133 Zinc (By similarity). FT METAL 143 143 Zinc (By similarity). FT BINDING 391 391 ATP (By similarity). FT MOD_RES 180 180 Phosphotyrosine; by autocatalysis. FT MOD_RES 512 512 Phosphotyrosine; by LCK. FT MOD_RES 565 565 Phosphoserine. FT VARIANT 19 19 R -> K (in a metastatic melanoma sample; FT somatic mutation). FT /FTId=VAR_041710. FT VARIANT 23 23 P -> L (in a metastatic melanoma sample; FT somatic mutation). FT /FTId=VAR_041711. FT VARIANT 193 193 R -> Q (in dbSNP:rs17054374). FT /FTId=VAR_051696. FT VARIANT 335 335 R -> W (in LPFS1; shows nearly FT undetectable mutant ITK protein FT consistent with severe protein FT instability; dbSNP:rs121908191). FT /FTId=VAR_063424. FT VARIANT 451 451 R -> Q (in a gastric adenocarcinoma FT sample; somatic mutation). FT /FTId=VAR_041712. FT VARIANT 581 581 R -> W (in dbSNP:rs34482255). FT /FTId=VAR_041713. FT VARIANT 587 587 V -> I (in dbSNP:rs56005928). FT /FTId=VAR_041714. FT MUTAGEN 288 288 P->G: Complete loss of interaction with FT PPIA/CYPA. FT CONFLICT 171 172 PE -> GS (in Ref. 6; AA sequence). FT CONFLICT 331 331 V -> W (in Ref. 2; AAB28072). FT STRAND 127 133 FT STRAND 148 152 FT STRAND 171 173 FT STRAND 175 180 FT STRAND 187 189 FT STRAND 197 205 FT STRAND 208 212 FT STRAND 214 216 FT STRAND 218 221 FT HELIX 223 225 FT STRAND 226 228 FT HELIX 360 362 FT STRAND 363 371 FT STRAND 372 374 FT STRAND 376 382 FT TURN 383 385 FT STRAND 386 393 FT TURN 395 397 FT HELIX 400 411 FT STRAND 421 425 FT STRAND 427 436 FT HELIX 443 448 FT TURN 449 452 FT HELIX 456 475 FT HELIX 485 487 FT STRAND 488 490 FT HELIX 492 494 FT STRAND 496 498 FT HELIX 503 506 FT HELIX 510 513 FT HELIX 522 524 FT HELIX 527 532 FT HELIX 537 552 FT TURN 553 555 FT TURN 558 561 FT HELIX 564 572 FT STRAND 581 583 FT HELIX 585 594 FT HELIX 599 601 FT HELIX 605 617 SQ SEQUENCE 620 AA; 71831 MW; DAE396BD2309319D CRC64; MNNFILLEEQ LIKKSQQKRR TSPSNFKVRF FVLTKASLAY FEDRHGKKRT LKGSIELSRI KCVEIVKSDI SIPCHYKYPF QVVHDNYLLY VFAPDRESRQ RWVLALKEET RNNNSLVPKY HPNFWMDGKW RCCSQLEKLA TGCAQYDPTK NASKKPLPPT PEDNRRPLWE PEETVVIALY DYQTNDPQEL ALRRNEEYCL LDSSEIHWWR VQDRNGHEGY VPSSYLVEKS PNNLETYEWY NKSISRDKAE KLLLDTGKEG AFMVRDSRTA GTYTVSVFTK AVVSENNPCI KHYHIKETND NPKRYYVAEK YVFDSIPLLI NYHQHNGGGL VTRLRYPVCF GRQKAPVTAG LRYGKWVIDP SELTFVQEIG SGQFGLVHLG YWLNKDKVAI KTIREGAMSE EDFIEEAEVM MKLSHPKLVQ LYGVCLEQAP ICLVFEFMEH GCLSDYLRTQ RGLFAAETLL GMCLDVCEGM AYLEEACVIH RDLAARNCLV GENQVIKVSD FGMTRFVLDD QYTSSTGTKF PVKWASPEVF SFSRYSSKSD VWSFGVLMWE VFSEGKIPYE NRSNSEVVED ISTGFRLYKP RLASTHVYQI MNHCWKERPE DRPAFSRLLR QLAEIAESGL //