Tyrosine-protein kinase CSK
|C-src tyrosine kinase|
PDB rendering based on 1byg.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Tyrosine-protein kinase CSK also known as C-Src kinase or C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene. This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.
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. 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.
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.
Expression and subcellular location
CSK is expressed in the lungs and macrophages as well as several other tissues. Tyrosine-Kinase CSK is mainly mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.
- Y184F – Abolishes phosphorylation.
- Y304F – Decreases activity by two-thirds and alters conformation.
- S364A – Strong decrease of phosphorylation by PRKACA (the catalytic subunit of protein kinase A).
- "Entrez Gene: C-src tyrosine kinase". Retrieved 2013-07-11.
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- Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H, Ikawa Y et al. (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.
- Chong YP, Chan AS, Chan KC, Williamson NA, Lerner EC, Smithgall TE et al. (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. PMID 16959780.
- 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.
- 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. PMID 1371489. Vancouver style error (help)
- 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 ( Pt 3): 927–35. PMC 1218276. PMID 9148770.
- Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skålhegg BS et al. (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. Vancouver style error (help)
- Fiorillo E, Orrú V, Stanford SM, Liu Y, Salek M, Rapini N et al. (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. Vancouver style error (help)