ITK_HUMAN
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 03-AUG-2022, entry version 222.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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 interleukin
RT 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-cell-
RT specific tyrosine kinase located at the hematopoietin complex on chromosome
RT 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., 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 [4]
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 [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 project:
RT 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 domain
RT 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., Venkatesan S.,
RA O'Day K., Schieven G.L., Lin T.A., Kanner S.B.;
RT "Phosphorylation of the linker for activation of T-cells by Itk promotes
RT recruitment of Vav.";
RL Biochemistry 41:10732-10740(2002).
RN [11]
RP FUNCTION.
RX PubMed=12682224; DOI=10.4049/jimmunol.170.8.3971;
RA Grasis J.A., Browne C.D., Tsoukas C.D.;
RT "Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal
RT 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 from
RT human T cells using immobilized metal affinity chromatography and tandem
RT 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 proline-
RT directed conformational switch in Itk.";
RL Immunity 21:189-201(2004).
RN [14]
RP INTERACTION WITH VAV1.
RX PubMed=15661896; DOI=10.4049/jimmunol.174.3.1385;
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., Schwartzberg P.L.;
RT "Kinase-independent functions for Itk in TCR-induced regulation of Vav and
RT 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 of
RT 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 (CD178) by
RT 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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 UBIQUITINATION.
RX PubMed=20596523; DOI=10.1371/journal.pone.0011332;
RA Del Rincon S.V., Rogers J., Widschwendter M., Sun D., Sieburg H.B.,
RA Spruck C.;
RT "Development and validation of a method for profiling post-translational
RT modification activities using protein microarrays.";
RL PLoS ONE 5:E11332-E11332(2010).
RN [20]
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., Smith-Garvin J.E.,
RA Okumura M., Starosvetsky E., Kosoff R., Libman E., Koretzky G.,
RA Kambayashi T., Urlaub H., Wienands J., Chernoff J., 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 [21]
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-protein
RT kinase ITK from human.";
RL Submitted (OCT-2007) to the PDB data bank.
RN [22]
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., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [23]
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., Laws H.-J.,
RA Telieps T., Knapp S., Wacker H.-H., Meindl A., Jumaa H., Borkhardt A.;
RT "Girls homozygous for an IL-2-inducible T cell kinase mutation that leads
RT to protein deficiency develop fatal EBV-associated lymphoproliferation.";
RL J. Clin. Invest. 119:1350-1358(2009).
CC -!- FUNCTION: Tyrosine kinase that plays an essential role in regulation of
CC the adaptive immune response. Regulates the development, function and
CC differentiation of conventional T-cells and nonconventional NKT-cells.
CC When antigen presenting cells (APC) activate T-cell receptor (TCR), a
CC series of phosphorylation lead to the recruitment of ITK to the cell
CC membrane, in the vicinity of the stimulated TCR receptor, where it is
CC phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation
CC and full activation. Once activated, phosphorylates PLCG1, leading to
CC the activation of this lipase and subsequent cleavage of its
CC substrates. In turn, the endoplasmic reticulum releases calcium in the
CC cytoplasm and the nuclear activator of activated T-cells (NFAT)
CC translocates into the nucleus to perform its transcriptional duty.
CC Phosphorylates 2 essential adapter proteins: the linker for activation
CC of T-cells/LAT protein and LCP2. Then, a large number of signaling
CC molecules such as VAV1 are recruited and ultimately lead to lymphokine
CC production, T-cell proliferation and differentiation (PubMed:12186560,
CC PubMed:12682224, PubMed:21725281). Required for TCR-mediated calcium
CC response in gamma-delta T-cells, may also be involved in the modulation
CC of the transcriptomic signature in the Vgamma2-positive subset of
CC immature gamma-delta T-cells (By similarity). Phosphorylates TBX21 at
CC 'Tyr-530' and mediates its interaction with GATA3 (By similarity).
CC {ECO:0000250|UniProtKB:Q03526, ECO:0000269|PubMed:12186560,
CC ECO:0000269|PubMed:12682224, ECO:0000269|PubMed:21725281}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250};
CC -!- SUBUNIT: Homooligomerizes; this association negatively regulates kinase
CC activity (By similarity). Interacts with PPIA/CYPA; this interaction
CC regulates TCR signal strength via a proline-directed conformational
CC switch in ITK. Interacts with THEMIS (By similarity). Interacts with
CC FASLG. Interacts with VAV1; this interaction is important for VAV1
CC localization and TCR-induced actin polarization. Interacts with TBX21
CC (By similarity). {ECO:0000250|UniProtKB:Q03526,
CC ECO:0000269|PubMed:15308100, ECO:0000269|PubMed:15661896,
CC ECO:0000269|PubMed:19807924}.
CC -!- INTERACTION:
CC Q08881; P04626: ERBB2; NbExp=2; IntAct=EBI-968552, EBI-641062;
CC Q08881; P48023: FASLG; NbExp=3; IntAct=EBI-968552, EBI-495538;
CC Q08881; P08238: HSP90AB1; NbExp=3; IntAct=EBI-968552, EBI-352572;
CC Q08881; Q13094: LCP2; NbExp=3; IntAct=EBI-968552, EBI-346946;
CC Q08881; P10686: Plcg1; Xeno; NbExp=2; IntAct=EBI-968552, EBI-520788;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17060314}. Nucleus
CC {ECO:0000250|UniProtKB:Q03526}. Note=Localizes in the vicinity of cell
CC surface receptors in the plasma membrane after receptor stimulation.
CC -!- TISSUE SPECIFICITY: T-cell lines and natural killer cell lines.
CC -!- INDUCTION: Through a myriad of surface receptors including the TCR/CD3
CC signaling complex, coreceptors, or chemokine receptors.
CC {ECO:0000269|PubMed:8504851, ECO:0000269|PubMed:9701039}.
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 also a
CC proline-rich region (PRR). The adjoining domain is a SH3 domain, which
CC binds to PRR (from itself or from other proteins). Next, a SH2 domain
CC is required for binding tyrosine-phosphorylated substrates. In the C-
CC terminal region, the kinase domain is required for tyrosine
CC phosphorylation. {ECO:0000269|PubMed:10795735}.
CC -!- PTM: Phosphorylated at Tyr-512 in the activation loop of the kinase
CC domain by LCK. Subsequent autophosphorylation at Tyr-180 leads to the
CC kinase activation. The autophosphorylated Tyr-180 lies within the
CC substrate binding sequence of the SH3 domain.
CC {ECO:0000269|PubMed:12573241, ECO:0000269|PubMed:9312162}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:20596523}.
CC -!- DISEASE: Lymphoproliferative syndrome 1 (LPFS1) [MIM:613011]: A rare
CC immunodeficiency characterized by extreme susceptibility to infection
CC with Epstein-Barr virus (EBV). Inadequate immune response to EBV can
CC have a fatal outcome. Clinical features include splenomegaly,
CC lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent
CC infections. There is an increased risk for lymphoma.
CC {ECO:0000269|PubMed:19425169}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. TEC subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ITKID43329ch5q33.html";
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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 CCDS; CCDS4336.1; -.
DR PIR; S33253; S33253.
DR RefSeq; NP_005537.3; NM_005546.3.
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 PDB; 4KIO; X-ray; 2.18 A; A/B/C/D=357-620.
DR PDB; 4L7S; X-ray; 2.03 A; A/B=357-620.
DR PDB; 4M0Y; X-ray; 1.70 A; A=354-620.
DR PDB; 4M0Z; X-ray; 2.00 A; A=354-620.
DR PDB; 4M12; X-ray; 2.15 A; A=354-620.
DR PDB; 4M13; X-ray; 1.85 A; A=354-620.
DR PDB; 4M14; X-ray; 1.55 A; A=354-620.
DR PDB; 4M15; X-ray; 1.52 A; A=354-620.
DR PDB; 4MF0; X-ray; 2.67 A; A/B=357-620.
DR PDB; 4MF1; X-ray; 2.11 A; A/B=357-620.
DR PDB; 4PP9; X-ray; 2.58 A; A/B=357-620.
DR PDB; 4PPA; X-ray; 2.67 A; A/B=357-620.
DR PDB; 4PPB; X-ray; 2.82 A; A/B=357-620.
DR PDB; 4PPC; X-ray; 2.95 A; A/B=357-620.
DR PDB; 4PQN; X-ray; 1.71 A; A=357-620.
DR PDB; 4QD6; X-ray; 2.45 A; A/B=357-620.
DR PDB; 4RFM; X-ray; 2.10 A; A=357-620.
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 PDBsum; 4KIO; -.
DR PDBsum; 4L7S; -.
DR PDBsum; 4M0Y; -.
DR PDBsum; 4M0Z; -.
DR PDBsum; 4M12; -.
DR PDBsum; 4M13; -.
DR PDBsum; 4M14; -.
DR PDBsum; 4M15; -.
DR PDBsum; 4MF0; -.
DR PDBsum; 4MF1; -.
DR PDBsum; 4PP9; -.
DR PDBsum; 4PPA; -.
DR PDBsum; 4PPB; -.
DR PDBsum; 4PPC; -.
DR PDBsum; 4PQN; -.
DR PDBsum; 4QD6; -.
DR PDBsum; 4RFM; -.
DR AlphaFoldDB; Q08881; -.
DR BMRB; Q08881; -.
DR SMR; Q08881; -.
DR BioGRID; 109907; 45.
DR CORUM; Q08881; -.
DR DIP; DIP-29974N; -.
DR IntAct; Q08881; 33.
DR MINT; Q08881; -.
DR STRING; 9606.ENSP00000398655; -.
DR BindingDB; Q08881; -.
DR ChEMBL; CHEMBL2959; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB06589; Pazopanib.
DR DrugBank; DB02010; Staurosporine.
DR DrugBank; DB15035; Zanubrutinib.
DR DrugCentral; Q08881; -.
DR GuidetoPHARMACOLOGY; 2046; -.
DR iPTMnet; Q08881; -.
DR PhosphoSitePlus; Q08881; -.
DR BioMuta; ITK; -.
DR DMDM; 585361; -.
DR jPOST; Q08881; -.
DR MassIVE; Q08881; -.
DR MaxQB; Q08881; -.
DR PaxDb; Q08881; -.
DR PeptideAtlas; Q08881; -.
DR PRIDE; Q08881; -.
DR ProteomicsDB; 58650; -.
DR ABCD; Q08881; 4 sequenced antibodies.
DR Antibodypedia; 16533; 511 antibodies from 42 providers.
DR DNASU; 3702; -.
DR Ensembl; ENST00000422843.8; ENSP00000398655.4; ENSG00000113263.13.
DR GeneID; 3702; -.
DR KEGG; hsa:3702; -.
DR MANE-Select; ENST00000422843.8; ENSP00000398655.4; NM_005546.4; NP_005537.3.
DR UCSC; uc003lwo.2; human.
DR CTD; 3702; -.
DR DisGeNET; 3702; -.
DR GeneCards; ITK; -.
DR HGNC; HGNC:6171; ITK.
DR HPA; ENSG00000113263; Tissue enriched (lymphoid).
DR MalaCards; ITK; -.
DR MIM; 186973; gene.
DR MIM; 613011; phenotype.
DR neXtProt; NX_Q08881; -.
DR OpenTargets; ENSG00000113263; -.
DR Orphanet; 538963; Combined immunodeficiency due to ITK deficiency.
DR PharmGKB; PA29968; -.
DR VEuPathDB; HostDB:ENSG00000113263; -.
DR eggNOG; KOG0197; Eukaryota.
DR GeneTree; ENSGT00940000158850; -.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; Q08881; -.
DR OMA; RMGKDER; -.
DR OrthoDB; 1047190at2759; -.
DR PhylomeDB; Q08881; -.
DR TreeFam; TF351634; -.
DR BRENDA; 2.7.10.2; 2681.
DR PathwayCommons; Q08881; -.
DR Reactome; R-HSA-202433; Generation of second messenger molecules.
DR Reactome; R-HSA-2871809; FCERI mediated Ca+2 mobilization.
DR SignaLink; Q08881; -.
DR SIGNOR; Q08881; -.
DR BioGRID-ORCS; 3702; 14 hits in 1105 CRISPR screens.
DR ChiTaRS; ITK; human.
DR EvolutionaryTrace; Q08881; -.
DR GeneWiki; ITK_(gene); -.
DR GenomeRNAi; 3702; -.
DR Pharos; Q08881; Tclin.
DR PRO; PR:Q08881; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q08881; protein.
DR Bgee; ENSG00000113263; Expressed in granulocyte and 128 other tissues.
DR ExpressionAtlas; Q08881; baseline and differential.
DR Genevisible; Q08881; HS.
DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
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:0004713; F:protein tyrosine kinase activity; IBA:GO_Central.
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:0050853; P:B cell receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0006968; P:cellular defense response; TAS:ProtInc.
DR GO; GO:0046629; P:gamma-delta T cell activation; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0001865; P:NK T cell differentiation; IBA:GO_Central.
DR GO; GO:0001819; P:positive regulation of cytokine production; ISS:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0042110; P:T cell activation; TAS:UniProtKB.
DR GO; GO:0050852; P:T cell receptor signaling pathway; ISS:UniProtKB.
DR CDD; cd05112; PTKc_Itk; 1.
DR CDD; cd11908; SH3_ITK; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR042785; ITK_PTKc.
DR InterPro; IPR035583; ITK_SH3.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
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; IPR036860; SH2_dom_sf.
DR InterPro; IPR036028; SH3-like_dom_sf.
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; PK_Tyr_Ser-Thr; 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; SSF55550; SSF55550; 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; Cytoplasm;
KW Direct protein sequencing; Disease variant; Immunity; Kinase;
KW Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; SH2 domain; SH3 domain; Transferase;
KW Tyrosine-protein kinase; Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..620
FT /note="Tyrosine-protein kinase ITK/TSK"
FT /id="PRO_0000088106"
FT DOMAIN 4..111
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 171..231
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 239..338
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 363..615
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ZN_FING 113..149
FT /note="Btk-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00432"
FT ACT_SITE 482
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 121
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00432"
FT BINDING 132
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00432"
FT BINDING 133
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00432"
FT BINDING 143
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00432"
FT BINDING 369..377
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 391
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 180
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12573241"
FT MOD_RES 512
FT /note="Phosphotyrosine; by LCK"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 565
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT VARIANT 19
FT /note="R -> K (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041710"
FT VARIANT 23
FT /note="P -> L (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041711"
FT VARIANT 193
FT /note="R -> Q (in dbSNP:rs17054374)"
FT /id="VAR_051696"
FT VARIANT 335
FT /note="R -> W (in LPFS1; shows nearly undetectable mutant
FT ITK protein consistent with severe protein instability;
FT dbSNP:rs121908191)"
FT /evidence="ECO:0000269|PubMed:19425169"
FT /id="VAR_063424"
FT VARIANT 451
FT /note="R -> Q (in a gastric adenocarcinoma sample; somatic
FT mutation; dbSNP:rs779372373)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041712"
FT VARIANT 581
FT /note="R -> W (in dbSNP:rs34482255)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041713"
FT VARIANT 587
FT /note="V -> I (in dbSNP:rs56005928)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041714"
FT MUTAGEN 288
FT /note="P->G: Complete loss of interaction with PPIA/CYPA."
FT /evidence="ECO:0000269|PubMed:15308100"
FT CONFLICT 171..172
FT /note="PE -> GS (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 331
FT /note="V -> W (in Ref. 2; AAB28072)"
FT /evidence="ECO:0000305"
FT STRAND 127..133
FT /evidence="ECO:0007829|PDB:2E6I"
FT STRAND 148..152
FT /evidence="ECO:0007829|PDB:2E6I"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:2YUQ"
FT STRAND 175..180
FT /evidence="ECO:0007829|PDB:2LMJ"
FT STRAND 187..189
FT /evidence="ECO:0007829|PDB:2YUQ"
FT STRAND 197..205
FT /evidence="ECO:0007829|PDB:2LMJ"
FT STRAND 208..212
FT /evidence="ECO:0007829|PDB:2LMJ"
FT STRAND 214..216
FT /evidence="ECO:0007829|PDB:2LMJ"
FT STRAND 218..221
FT /evidence="ECO:0007829|PDB:2LMJ"
FT HELIX 223..225
FT /evidence="ECO:0007829|PDB:2LMJ"
FT STRAND 226..228
FT /evidence="ECO:0007829|PDB:2LMJ"
FT HELIX 360..362
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 363..371
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 373..375
FT /evidence="ECO:0007829|PDB:4KIO"
FT STRAND 376..382
FT /evidence="ECO:0007829|PDB:4HCU"
FT TURN 383..385
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 386..393
FT /evidence="ECO:0007829|PDB:4HCU"
FT TURN 395..397
FT /evidence="ECO:0007829|PDB:3T9T"
FT HELIX 400..411
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 421..425
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 427..436
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 443..448
FT /evidence="ECO:0007829|PDB:4HCU"
FT TURN 449..452
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 456..475
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 485..487
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 488..490
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 492..494
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 496..498
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 503..506
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 510..513
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 522..524
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 527..532
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 537..552
FT /evidence="ECO:0007829|PDB:4HCU"
FT TURN 553..555
FT /evidence="ECO:0007829|PDB:4PQN"
FT TURN 558..561
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 564..572
FT /evidence="ECO:0007829|PDB:4HCU"
FT STRAND 581..583
FT /evidence="ECO:0007829|PDB:3V8W"
FT HELIX 585..594
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 599..601
FT /evidence="ECO:0007829|PDB:4HCU"
FT HELIX 605..617
FT /evidence="ECO:0007829|PDB:4HCU"
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
