ITK (gene)

ITK
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1SM2, 1SNU, 1SNX, 2E6I, 2LMJ, 2YUQ, 3MIY, 3MJ1, 3MJ2, 3QGW, 3QGY, 3T9T, 3V5J, 3V5L, 3V8T, 3V8W, 4HCT, 4HCU, 4HCV, 4KIO, 4L7S, 4M0Y, 4M0Z, 4M12, 4M13, 4M14, 4M15, 4MF0, 4MF1, 4PP9, 4PPA, 4PPB, 4PPC, 4PQN, 4QD6, 4RFM
Identifiers
Aliases	ITK , EMT, LPFS1, LYK, PSCTK2, IL2 inducible T-cell kinase, IL2 inducible T cell kinase
External IDs	OMIM: 186973; MGI: 96621; HomoloGene: 4051; GeneCards: ITK; OMA:ITK - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5q33.3 Start 157,142,933 bp [1] End 157,255,185 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11 B1.1|11 27.75 cM Start 46,215,977 bp [2] End 46,280,342 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte thymus blood lymph node appendix spleen epithelium of colon bone marrow cells superficial temporal artery gallbladder Top expressed in thymus mesenteric lymph nodes blood spleen granulocyte submandibular gland subcutaneous adipose tissue perirhinal cortex entorhinal cortex Ileal epithelium More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity non-membrane spanning protein tyrosine kinase activity metal ion binding kinase activity protein binding protein tyrosine kinase activity signaling receptor binding ATP binding Cellular component cytoplasm cytosol cell-cell junction extrinsic component of cytoplasmic side of plasma membrane nucleus Biological process intracellular signal transduction adaptive immune response phosphorylation NK T cell differentiation transmembrane receptor protein tyrosine kinase signaling pathway immune system process cytokine production activation of phospholipase C activity Fc-epsilon receptor signaling pathway protein phosphorylation cellular defense response regulation of cell population proliferation peptidyl-tyrosine autophosphorylation T cell receptor signaling pathway T cell activation signal transduction interleukin-4 production innate immune response B cell receptor signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3702 16428 Ensembl ENSG00000113263 ENSMUSG00000020395 UniProt Q08881 Q03526 RefSeq (mRNA) NM_005546 NM_001281965 NM_001281966 NM_001281967 NM_001281968 NM_010583 RefSeq (protein) NP_005537 NP_001268894 NP_001268895 NP_001268896 NP_001268897 NP_034713 Location (UCSC) Chr 5: 157.14 – 157.26 Mb Chr 11: 46.22 – 46.28 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tyrosine-protein kinase ITK/TSK also known as interleukin-2-inducible T-cell kinase or simply ITK, is a protein that in humans is encoded by the ITK gene. ^[5] ITK is a member of the TEC family of kinases and is highly expressed in T cells. ^[6]

Function

This gene encodes an intracellular tyrosine kinase expressed in T-cells. The protein is thought to play a role in T-cell proliferation and differentiation. ^{[7] [8]} ITK is functionally important for the development and effector function of T_h2 and T_h17 cells. ^[6]

Mice lacking ITK were shown to not be susceptible to asthma. ^[9]

Structure

This protein contains the following domains, which are often found in intracellular kinases: ^[10]

• N-terminus – PH (pleckstrin homology domain)
• TH – Tec family homology domain (including Bruton's tyrosine kinase Cys-rich motif and Proline rich region)
• SH3 – (Src homology 3)
• SH2 – (Src homology 2)
• C-terminus – tyrosine kinase, catalytic domain

Interactions

ITK (gene) has been shown to interact with:

• FYN, ^{[11] [12]}
• Grb2 ^{[11] [13]} and
• KHDRBS1, ^{[12] [13] [14]}
• KPNA2, ^[15]
• LAT, ^{[16] [17]}
• LCP2, ^{[11] [18]}
• PLCG1, ^{[14] [19]}
• PPIA, ^[20] and
• WAS. ^{[12] [21]}

Inhibitors

• Soquelitinib (CPI-818)

References

1. GRCh38: Ensembl release 89: ENSG00000113263 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000020395 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Gibson S, Leung B, Squire JA, Hill M, Arima N, Goss P, Hogg D, Mills GB (September 1993). "Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q" . Blood. 82 (5): 1561–72. doi: 10.1182/blood.V82.5.1561.1561 . PMID   8364206.
6. Gomez-Rodriguez J, Kraus ZJ, Schwartzberg PL (March 2011). "Tec family kinases Itk and Rlk/Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates". The FEBS Journal. 278 (12): 1980–1989. doi:10.1111/j.1742-4658.2011.08072.x. PMC   3117960 . PMID   21362139.
7. Kosaka Y, Felices M, Berg LJ (October 2006). "Itk and Th2 responses: action but no reaction". Trends Immunol. 27 (10): 453–60. doi:10.1016/j.it.2006.08.006. PMID   16931156.
8. "Entrez Gene: ITK IL2-inducible T-cell kinase".
9. Mueller C, August A (2003-05-15). "Attenuation of immunological symptoms of allergic asthma in mice lacking the tyrosine kinase ITK". Journal of Immunology. 170 (10): 5056–5063. doi: 10.4049/jimmunol.170.10.5056 . ISSN   0022-1767. PMID   12734350.
10. Hawkins J, Marcy A (July 2001). "Characterization of Itk tyrosine kinase: contribution of noncatalytic domains to enzymatic activity". Protein Expr. Purif. 22 (2): 211–9. doi:10.1006/prep.2001.1447. PMID   11437596.
11. Bunnell SC, Diehn M, Yaffe MB, Findell PR, Cantley LC, Berg LJ (2000). "Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade". J. Biol. Chem. 275 (3): 2219–30. doi: 10.1074/jbc.275.3.2219 . PMID   10636929.
12. Bunnell SC, Henry PA, Kolluri R, Kirchhausen T, Rickles RJ, Berg LJ (1996). "Identification of Itk/Tsk Src homology 3 domain ligands". J. Biol. Chem. 271 (41): 25646–56. doi: 10.1074/jbc.271.41.25646 . PMID   8810341.
13. Andreotti AH, Bunnell SC, Feng S, Berg LJ, Schreiber SL (1997). "Regulatory intramolecular association in a tyrosine kinase of the Tec family". Nature. 385 (6611): 93–7. Bibcode:1997Natur.385...93A. doi:10.1038/385093a0. PMID   8985255. S2CID   25356409.
14. Hao S, August A (2002). "The proline rich region of the Tec homology domain of ITK regulates its activity". FEBS Lett. 525 (1–3): 53–8. Bibcode:2002FEBSL.525...53H. doi: 10.1016/S0014-5793(02)03066-1 . PMID   12163161. S2CID   21541455.
15. Perez-Villar JJ, O'Day K, Hewgill DH, Nadler SG, Kanner SB (2001). "Nuclear localization of the tyrosine kinase Itk and interaction of its SH3 domain with karyopherin alpha (Rch1alpha)". Int. Immunol. 13 (10): 1265–74. doi: 10.1093/intimm/13.10.1265 . PMID   11581171.
16. Shan X, Wange RL (1999). "Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment". J. Biol. Chem. 274 (41): 29323–30. doi: 10.1074/jbc.274.41.29323 . PMID   10506192.
17. Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB (2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry. 41 (34): 10732–40. doi:10.1021/bi025554o. PMID   12186560.
18. Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR (2004). "Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase". FEBS Lett. 575 (1–3): 35–40. Bibcode:2004FEBSL.575...35S. doi: 10.1016/j.febslet.2004.07.090 . PMID   15388330. S2CID   24678709.
19. Perez-Villar JJ, Kanner SB (1999). "Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes". J. Immunol. 163 (12): 6435–41. doi: 10.4049/jimmunol.163.12.6435 . PMID   10586033.
20. Brazin KN, Mallis RJ, Fulton DB, Andreotti AH (2002). "Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A". Proc. Natl. Acad. Sci. U.S.A. 99 (4): 1899–904. Bibcode:2002PNAS...99.1899B. doi: 10.1073/pnas.042529199 . PMC   122291 . PMID   11830645.
21. Cory GO, MacCarthy-Morrogh L, Banin S, Gout I, Brickell PM, Levinsky RJ, Kinnon C, Lovering RC (1996). "Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways". J. Immunol. 157 (9): 3791–5. doi: 10.4049/jimmunol.157.9.3791 . PMID   8892607.

Further reading

• Kosaka Y, Felices M, Berg LJ (2006). "Itk and Th2 responses: action but no reaction". Trends Immunol. 27 (10): 453–60. doi:10.1016/j.it.2006.08.006. PMID   16931156.
• Janis EM, Siliciano JD, Isaac DD, et al. (1995). "Mapping of the gene for the tyrosine kinase Itk to a region of conserved synteny between mouse chromosome 11 and human chromosome 5q". Genomics. 23 (1): 269–71. doi: 10.1006/geno.1994.1492 . PMID   7829087.
• Gibson S, Leung B, Squire JA, et al. (1993). "Identification, cloning, and characterization of a novel human T-cell-specific tyrosine kinase located at the hematopoietin complex on chromosome 5q". Blood. 82 (5): 1561–72. doi: 10.1182/blood.V82.5.1561.1561 . PMID   8364206.
• Tanaka N, Asao H, Ohtani K, et al. (1993). "A novel human tyrosine kinase gene inducible in T cells by interleukin 2". FEBS Lett. 324 (1): 1–5. Bibcode:1993FEBSL.324....1T. doi: 10.1016/0014-5793(93)81520-A . PMID   8504851. S2CID   32621307.
• Bunnell SC, Henry PA, Kolluri R, et al. (1996). "Identification of Itk/Tsk Src homology 3 domain ligands". J. Biol. Chem. 271 (41): 25646–56. doi: 10.1074/jbc.271.41.25646 . PMID   8810341.
• Andreotti AH, Bunnell SC, Feng S, et al. (1997). "Regulatory intramolecular association in a tyrosine kinase of the Tec family". Nature. 385 (6611): 93–7. Bibcode:1997Natur.385...93A. doi:10.1038/385093a0. PMID   8985255. S2CID   25356409.
• Heyeck SD, Wilcox HM, Bunnell SC, Berg LJ (1997). "Lck phosphorylates the activation loop tyrosine of the Itk kinase domain and activates Itk kinase activity". J. Biol. Chem. 272 (40): 25401–8. doi: 10.1074/jbc.272.40.25401 . PMID   9312162.
• Kaukonen J, Savolainen ER, Palotie A (1999). "Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies". Leuk. Lymphoma. 32 (5–6): 513–22. doi:10.3109/10428199909058409. PMID   10048424.
• Shan X, Wange RL (1999). "Itk/Emt/Tsk activation in response to CD3 cross-linking in Jurkat T cells requires ZAP-70 and Lat and is independent of membrane recruitment". J. Biol. Chem. 274 (41): 29323–30. doi: 10.1074/jbc.274.41.29323 . PMID   10506192.
• Su YW, Zhang Y, Schweikert J, et al. (1999). "Interaction of SLP adaptors with the SH2 domain of Tec family kinases". Eur. J. Immunol. 29 (11): 3702–11. doi: 10.1002/(SICI)1521-4141(199911)29:11<3702::AID-IMMU3702>3.0.CO;2-R . PMID   10556826.
• Perez-Villar JJ, Kanner SB (2000). "Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes". J. Immunol. 163 (12): 6435–41. doi: 10.4049/jimmunol.163.12.6435 . PMID   10586033.
• Rajagopal K, Sommers CL, Decker DC, et al. (2000). "RIBP, a novel Rlk/Txk- and itk-binding adaptor protein that regulates T cell activation". J. Exp. Med. 190 (11): 1657–68. doi:10.1084/jem.190.11.1657. PMC   2195727 . PMID   10587356.
• Bunnell SC, Diehn M, Yaffe MB, et al. (2000). "Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade". J. Biol. Chem. 275 (3): 2219–30. doi: 10.1074/jbc.275.3.2219 . PMID   10636929.
• Shan X, Czar MJ, Bunnell SC, et al. (2000). "Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation". Mol. Cell. Biol. 20 (18): 6945–57. doi:10.1128/MCB.20.18.6945-6957.2000. PMC   88770 . PMID   10958690.
• Hawkins J, Marcy A (2001). "Characterization of Itk tyrosine kinase: contribution of noncatalytic domains to enzymatic activity". Protein Expr. Purif. 22 (2): 211–9. doi:10.1006/prep.2001.1447. PMID   11437596.