Tyrosine-protein kinase CSK

This article is about the kinase CSK, for the kinase that is phosphorylated by CSK, see c-Src.

Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene.^[5] This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.^[6][7]

CSK
Available structures PDB Ortholog search: H3BU69 PDBe H3BU69 RCSB List of PDB id codes 1BYG, 1CSK, 3D7T, 3D7U, 3EAC, 3EAZ
Identifiers
Aliases	CSK, Src, c-src tyrosine kinase, CSK/Src, non-receptor tyrosine kinase, C-terminal Src kinase
External IDs	OMIM: 190090, 124095; MGI: 88537; HomoloGene: 55818; GeneCards: CSK; OMA:CSK - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q24.1 Start 74,782,057 bp[1] End 74,803,198 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 B|9 31.18 cM Start 57,533,929 bp[2] End 57,560,914 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte monocyte spleen blood lymph node appendix mucosa of transverse colon tonsil bone marrow cells stromal cell of endometrium Top expressed in granulocyte mesenteric lymph nodes thymus spleen neural layer of retina lip ventricular zone blood yolk sac gastrula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity protein kinase A catalytic subunit binding non-membrane spanning protein tyrosine kinase activity metal ion binding protein C-terminus binding protein binding identical protein binding protein tyrosine kinase activity protein phosphatase binding proline-rich region binding signaling receptor binding ATP binding kinase activity Cellular component cytoplasm cytosol membrane cell-cell junction extrinsic component of cytoplasmic side of plasma membrane plasma membrane membrane raft extracellular exosome Biological process cell differentiation adaptive immune response positive regulation of MAP kinase activity epidermal growth factor receptor signaling pathway negative regulation of phagocytosis phosphorylation transmembrane receptor protein tyrosine kinase signaling pathway negative regulation of low-density lipoprotein particle clearance immune system process negative regulation of interleukin-6 production T cell costimulation oligodendrocyte differentiation negative regulation of Golgi to plasma membrane protein transport regulation of Fc receptor mediated stimulatory signaling pathway regulation of cytokine production protein phosphorylation brain development cellular response to peptide hormone stimulus regulation of cell population proliferation peptidyl-tyrosine autophosphorylation negative regulation of ERK1 and ERK2 cascade protein autophosphorylation innate immune response adherens junction organization T cell receptor signaling pathway negative regulation of cell population proliferation negative regulation of bone resorption negative regulation of kinase activity central nervous system development peptidyl-tyrosine phosphorylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1445 12988 Ensembl ENSG00000103653 ENSMUSG00000032312 UniProt P41240 P41241 RefSeq (mRNA) NM_001127190 NM_004383 NM_001354988 NM_007783 NM_001304761 RefSeq (protein) NP_001120662 NP_004374 NP_001341917 NP_001291690 NP_031809 Location (UCSC) Chr 15: 74.78 – 74.8 Mb Chr 9: 57.53 – 57.56 Mb PubMed search [3] [4]
Wikidata
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Function

This Non-receptor tyrosine-protein kinase plays an important role in the regulation of cell growth, differentiation, migration and immune response. CSK acts by suppressing the activity of the Src family of protein kinases by phosphorylation of Src family members at a conserved C-terminal tail site in Src.^{[8][9][10][11]} Upon phosphorylation by other kinases, Src-family members engage in intramolecular interactions between the phosphotyrosine tail and the SH2 domain that result in an inactive conformation. To inhibit SFKs, CSK is then recruited to the plasma membrane via binding to transmembrane proteins or adapter proteins located near the plasma membrane and ultimately suppresses signaling through various surface receptors, including T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and maintaining inactive several effector molecules.^[6][7]

Role in development and regulation

Tyrosine-protein kinase CSK is involved in the following developmental, metabolic, and signal transduction cascades:

Adherens junction organization, blood coagulation, brain development, cell differentiation, cell migration, cellular response to peptide hormone stimulus, central nervous system development, epidermal growth factor receptor signaling pathway, innate immune response, epithelium morphogenesis, regulation of bone resorption, negative regulation of cell proliferation, negative regulation of ERK1 and ERK2 cascade, negative regulation of Golgi to plasma membrane protein transport, negative regulation of interleukin-6 production, negative regulation of kinase activity, negative regulation of low-density lipoprotein particle clearance, negative regulation of phagocytosis, dendrocyte differentiation, peptidyl-tyrosine autophosphorylation, platelet activation, positive regulation of MAP kinase activity, regulation of cell proliferation, regulation of cytokine production, regulation of Fc receptor mediated stimulatory signaling pathway, T cell costimulation, T cell receptor signaling pathway.^[12]

Expression and subcellular location

CSK is expressed in the lungs and macrophages as well as several other tissues.^[13] Tyrosine-Kinase CSK is mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.^[12]

Mutations

• Y184F – Abolishes phosphorylation.^[14]
• Y304F – Decreases activity by two-thirds and alters conformation.^[14]
• S364A – Strong decrease of phosphorylation by PRKACA (the catalytic subunit of protein kinase A).^[15]

Clinical significance

Csk's interaction with a phosphatase ("Lyp", gene product of PTPN22) is possibly associated with the increased autoimmune diseases associated with PTPN22 mutations.^[16]

References

1. GRCh38: Ensembl release 89: ENSG00000103653 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032312 – 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. "Entrez Gene: C-src tyrosine kinase". Retrieved 2013-07-11.
6. Bergman M, Mustelin T, Oetken C, Partanen J, Flint NA, Amrein KE, Autero M, Burn P, Alitalo K (Aug 1992). "The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity". The EMBO Journal. 11 (8): 2919–24. doi:10.1002/j.1460-2075.1992.tb05361.x. PMC 556773. PMID 1639064.
7. Sun G, Budde RJ (Sep 1997). "Expression, purification, and initial characterization of human Yes protein tyrosine kinase from a bacterial expression system". Archives of Biochemistry and Biophysics. 345 (1): 135–42. doi:10.1006/abbi.1997.0236. PMID 9281320.
8. Nada S, Okada M, MacAuley A, Cooper JA, Nakagawa H (May 1991). "Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src". Nature. 351 (6321): 69–72. Bibcode:1991Natur.351...69N. doi:10.1038/351069a0. PMID 1709258. S2CID 4363527.
9. Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H, Ikawa Y, Okada M, Aizawa S (Jun 1993). "Constitutive activation of Src family kinases in mouse embryos that lack Csk". Cell. 73 (6): 1125–35. doi:10.1016/0092-8674(93)90642-4. PMID 8513497. S2CID 37988394.
10. Chong YP, Chan AS, Chan KC, Williamson NA, Lerner EC, Smithgall TE, Bjorge JD, Fujita DJ, Purcell AW, Scholz G, Mulhern TD, Cheng HC (Nov 2006). "C-terminal Src kinase-homologous kinase (CHK), a unique inhibitor inactivating multiple active conformations of Src family tyrosine kinases". The Journal of Biological Chemistry. 281 (44): 32988–99. doi:10.1074/jbc.M602951200. PMC 4281726. PMID 16959780.
11. Chong YP, Mulhern TD, Cheng HC (Sep 2005). "C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)--endogenous negative regulators of Src-family protein kinases". Growth Factors. 23 (3): 233–44. doi:10.1080/08977190500178877. PMID 16243715. S2CID 38227036.
12. Universal protein resource accession number P41240 for "Tyrosine-protein kinase CSK" at UniProt.
13. Bräuninger A, Holtrich U, Strebhardt K, Rübsamen-Waigmann H (Jan 1992). "Isolation and characterization of a human gene that encodes a new subclass of protein tyrosine kinases". Gene. 110 (2): 205–11. doi:10.1016/0378-1119(92)90649-a. PMID 1371489.
14. Joukov V, Vihinen M, Vainikka S, Sowadski JM, Alitalo K, Bergman M (Mar 1997). "Identification of csk tyrosine phosphorylation sites and a tyrosine residue important for kinase domain structure". The Biochemical Journal. 322 (3): 927–35. doi:10.1042/bj3220927. PMC 1218276. PMID 9148770.
15. Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skålhegg BS, Hansson V, Mustelin T, Taskén K (Feb 2001). "Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor". The Journal of Experimental Medicine. 193 (4): 497–507. doi:10.1084/jem.193.4.497. PMC 2195911. PMID 11181701.
16. Fiorillo E, Orrú V, Stanford SM, Liu Y, Salek M, Rapini N, Schenone AD, Saccucci P, Delogu LG, Angelini F, Manca Bitti ML, Schmedt C, Chan AC, Acuto O, Bottini N (Aug 2010). "Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue". The Journal of Biological Chemistry. 285 (34): 26506–18. doi:10.1074/jbc.M110.111104. PMC 2924087. PMID 20538612.

External links

• CSK tyrosine-protein kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)