Tyrosine-protein kinase ITK/TSK

Details

Name

Tyrosine-protein kinase ITK/TSK

Synonyms

• 2.7.10.2
• EMT
• IL-2-inducible T-cell kinase
• Interleukin-2-inducible T-cell kinase
• Kinase EMT
• LYK
• T-cell-specific kinase
• Tyrosine-protein kinase Lyk

Gene Name

ITK

Organism

Humans

Amino acid sequence

>lcl|BSEQ0010935|Tyrosine-protein kinase ITK/TSK
MNNFILLEEQLIKKSQQKRRTSPSNFKVRFFVLTKASLAYFEDRHGKKRTLKGSIELSRI
KCVEIVKSDISIPCHYKYPFQVVHDNYLLYVFAPDRESRQRWVLALKEETRNNNSLVPKY
HPNFWMDGKWRCCSQLEKLATGCAQYDPTKNASKKPLPPTPEDNRRPLWEPEETVVIALY
DYQTNDPQELALRRNEEYCLLDSSEIHWWRVQDRNGHEGYVPSSYLVEKSPNNLETYEWY
NKSISRDKAEKLLLDTGKEGAFMVRDSRTAGTYTVSVFTKAVVSENNPCIKHYHIKETND
NPKRYYVAEKYVFDSIPLLINYHQHNGGGLVTRLRYPVCFGRQKAPVTAGLRYGKWVIDP
SELTFVQEIGSGQFGLVHLGYWLNKDKVAIKTIREGAMSEEDFIEEAEVMMKLSHPKLVQ
LYGVCLEQAPICLVFEFMEHGCLSDYLRTQRGLFAAETLLGMCLDVCEGMAYLEEACVIH
RDLAARNCLVGENQVIKVSDFGMTRFVLDDQYTSSTGTKFPVKWASPEVFSFSRYSSKSD
VWSFGVLMWEVFSEGKIPYENRSNSEVVEDISTGFRLYKPRLASTHVYQIMNHCWKERPE
DRPAFSRLLRQLAEIAESGL

Number of residues

620

Molecular Weight

71830.405

Theoretical pI

7.63

GO Classification

Functions

ATP binding / metal ion binding / non-membrane spanning protein tyrosine kinase activity

Processes

activation of phospholipase C activity / adaptive immune response / cellular defense response / cytokine production / Fc-epsilon receptor signaling pathway / innate immune response / interferon-gamma production / interleukin-4 production / intracellular signal transduction / NK T cell differentiation / peptidyl-tyrosine autophosphorylation / regulation of cell proliferation / signal transduction / T cell activation / T cell receptor signaling pathway / transmembrane receptor protein tyrosine kinase signaling pathway

Components

cell-cell junction / cytosol / extrinsic component of cytoplasmic side of plasma membrane

General Function

Non-membrane spanning protein tyrosine kinase activity

Specific Function

Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.

Pfam Domain Function

• PK_Tyr_Ser-Thr (PF07714)
• SH2 (PF00017)
• SH3_1 (PF00018)
• PH (PF00169)
• BTK (PF00779)

Transmembrane Regions

Not Available

Cellular Location

Cytoplasm

Gene sequence

>lcl|BSEQ0010936|Tyrosine-protein kinase ITK/TSK (ITK)
ATGAACAACTTTATCCTCCTGGAAGAACAGCTCATCAAGAAATCCCAACAAAAGAGAAGA
ACTTCTCCCTCGAACTTTAAAGTCCGCTTCTTTGTGTTAACCAAAGCCAGCCTGGCATAC
TTTGAAGATCGTCATGGGAAGAAGCGCACGCTGAAGGGGTCCATTGAGCTCTCCCGAATC
AAATGTGTTGAGATTGTGAAAAGTGACATCAGCATCCCATGCCACTATAAATACCCGTTT
CAGGTGGTGCATGACAACTACCTCCTATATGTGTTTGCTCCAGATCGTGAGAGCCGGCAG
CGCTGGGTGCTGGCCCTTAAAGAAGAAACGAGGAATAATAACAGTTTGGTGCCTAAATAT
CATCCTAATTTCTGGATGGATGGGAAGTGGAGGTGCTGTTCTCAGCTGGAGAAGCTTGCA
ACAGGCTGTGCCCAATATGATCCAACCAAGAATGCTTCAAAGAAGCCTCTTCCTCCTACT
CCTGAAGACAACAGGCGACCACTTTGGGAACCTGAAGAAACTGTGGTCATTGCCTTATAT
GACTACCAAACCAATGATCCTCAGGAACTCGCACTGCGGCGCAACGAAGAGTACTGCCTG
CTGGACAGTTCTGAGATTCACTGGTGGAGAGTCCAGGACAGGAATGGGCATGAAGGATAT
GTACCAAGCAGTTATCTGGTGGAAAAATCTCCAAATAATCTGGAAACCTATGAGTGGTAC
AATAAGAGTATCAGCCGAGACAAAGCTGAAAAACTTCTTTTGGACACAGGCAAAGAAGGA
GCCTTCATGGTAAGGGATTCCAGGACTGCAGGAACATACACCGTGTCTGTTTTCACCAAG
GCTGTTGTAAGTGAGAACAATCCCTGTATAAAGCATTATCACATCAAGGAAACAAATGAC
AATCCTAAGCGATACTATGTGGCTGAAAAGTATGTGTTCGATTCCATCCCTCTTCTCATC
AACTATCACCAACATAATGGAGGAGGCCTGGTGACTCGACTCCGGTATCCAGTTTGTTTT
GGGAGGCAGAAAGCCCCAGTTACAGCAGGGCTGAGATACGGGAAATGGGTGATCGACCCC
TCAGAGCTCACTTTTGTGCAAGAGATTGGCAGTGGGCAATTTGGGTTGGTGCATCTGGGC
TACTGGCTCAACAAGGACAAGGTGGCTATCAAAACCATTCGGGAAGGGGCTATGTCAGAA
GAGGACTTCATAGAGGAGGCTGAAGTAATGATGAAACTCTCTCATCCCAAACTGGTGCAG
CTGTATGGGGTGTGCCTGGAGCAGGCCCCCATCTGCCTGGTGTTTGAGTTCATGGAGCAC
GGCTGCCTGTCAGATTATCTACGCACCCAGCGGGGACTTTTTGCTGCAGAGACCCTGCTG
GGCATGTGTCTGGATGTGTGTGAGGGCATGGCCTACCTGGAAGAGGCATGTGTCATCCAC
AGAGACTTGGCTGCCAGAAATTGTTTGGTGGGAGAAAACCAAGTCATCAAGGTGTCTGAC
TTTGGGATGACAAGGTTCGTTCTGGATGATCAGTACACCAGTTCCACAGGCACCAAATTC
CCGGTGAAGTGGGCATCCCCAGAGGTTTTCTCTTTCAGTCGCTATAGCAGCAAGTCCGAT
GTGTGGTCATTTGGTGTGCTGATGTGGGAAGTTTTCAGTGAAGGCAAAATCCCGTATGAA
AACCGAAGCAACTCAGAGGTGGTGGAAGACATCAGTACCGGATTTCGGTTGTACAAGCCC
CGGCTGGCCTCCACACACGTCTACCAGATTATGAATCACTGCTGGAAAGAGAGACCAGAA
GATCGGCCAGCCTTCTCCAGACTGCTGCGTCAACTGGCTGAAATTGCAGAATCAGGACTT
TAG

Chromosome Location

5

Locus

5q31-q32

External Identifiers

Resource	Link
UniProtKB ID	Q08881
UniProtKB Entry Name	ITK_HUMAN
GenBank Protein ID	399658
GenBank Gene ID	D13720
GenAtlas ID	ITK
HGNC ID	HGNC:6171

General References

1. Tanaka N, Asao H, Ohtani K, Nakamura M, Sugamura K: A novel human tyrosine kinase gene inducible in T cells by interleukin 2. FEBS Lett. 1993 Jun 7;324(1):1-5. [Article]
2. Gibson S, Leung B, Squire JA, Hill M, Arima N, Goss P, Hogg D, Mills GB: Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q. Blood. 1993 Sep 1;82(5):1561-72. [Article]
3. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
4. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
5. Nore BF, Mattsson PT, Antonsson P, Backesjo CM, Westlund A, Lennartsson J, Hansson H, Low P, Ronnstrand L, Smith CI: Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases. Biochim Biophys Acta. 2003 Feb 21;1645(2):123-32. [Article]
6. Heyeck SD, Wilcox HM, Bunnell SC, Berg LJ: Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity. J Biol Chem. 1997 Oct 3;272(40):25401-8. [Article]
7. King PD, Sadra A, Teng JM, Bell GM, Dupont B: CD2-mediated activation of the Tec-family tyrosine kinase ITK is controlled by proline-rich stretch-4 of the CD2 cytoplasmic tail. Int Immunol. 1998 Jul;10(7):1009-16. [Article]
8. Yang WC, Collette Y, Nunes JA, Olive D: Tec kinases: a family with multiple roles in immunity. Immunity. 2000 Apr;12(4):373-82. [Article]
9. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB: Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. Biochemistry. 2002 Aug 27;41(34):10732-40. [Article]
10. Grasis JA, Browne CD, Tsoukas CD: Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor. J Immunol. 2003 Apr 15;170(8):3971-6. [Article]
11. Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M, Peters EC: Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry. Anal Chem. 2004 May 15;76(10):2763-72. [Article]
12. Colgan J, Asmal M, Neagu M, Yu B, Schneidkraut J, Lee Y, Sokolskaja E, Andreotti A, Luban J: Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk. Immunity. 2004 Aug;21(2):189-201. [Article]
13. Dombroski D, Houghtling RA, Labno CM, Precht P, Takesono A, Caplen NJ, Billadeau DD, Wange RL, Burkhardt JK, Schwartzberg PL: Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. J Immunol. 2005 Feb 1;174(3):1385-92. [Article]
14. Qi Q, Sahu N, August A: Tec kinase Itk forms membrane clusters specifically in the vicinity of recruiting receptors. J Biol Chem. 2006 Dec 15;281(50):38529-34. Epub 2006 Oct 23. [Article]
15. Voss M, Lettau M, Janssen O: Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening. BMC Immunol. 2009 Oct 6;10:53. doi: 10.1186/1471-2172-10-53. [Article]
16. Joseph RE, Severin A, Min L, Fulton DB, Andreotti AH: SH2-dependent autophosphorylation within the Tec family kinase Itk. J Mol Biol. 2009 Aug 7;391(1):164-77. doi: 10.1016/j.jmb.2009.06.023. Epub 2009 Jun 11. [Article]
17. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [Article]
18. Del Rincon SV, Rogers J, Widschwendter M, Sun D, Sieburg HB, Spruck C: Development and validation of a method for profiling post-translational modification activities using protein microarrays. PLoS One. 2010 Jun 28;5(6):e11332. doi: 10.1371/journal.pone.0011332. [Article]
19. Sela M, Bogin Y, Beach D, Oellerich T, Lehne J, Smith-Garvin JE, Okumura M, Starosvetsky E, Kosoff R, Libman E, Koretzky G, Kambayashi T, Urlaub H, Wienands J, Chernoff J, Yablonski D: Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J. 2011 Jul 1;30(15):3160-72. doi: 10.1038/emboj.2011.213. [Article]
20. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR: Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8. [Article]
21. Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, Telieps T, Knapp S, Wacker HH, Meindl A, Jumaa H, Borkhardt A: Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009 May;119(5):1350-8. [Article]

Drug Relations

Drug Relations

DrugBank ID	Name	Drug group	Pharmacological action?	Actions	Details
DB02010	Staurosporine	experimental	unknown		Details
DB06589	Pazopanib	approved	unknown	inhibitor	Details
DB12010	Fostamatinib	approved, investigational	unknown	inhibitor	Details
DB15035	Zanubrutinib	approved, investigational	unknown	inhibitor	Details
DB14924	Ritlecitinib	approved, investigational	yes	inhibitor	Details