Tyrosine-protein kinase CSK explained
Tyrosine-protein kinase CSK also known as C-terminal Src kinase is an enzyme that, in humans, is encoded by the CSK gene.[1] This enzyme phosphorylates tyrosine residues located in the C-terminal end of Src-family kinases (SFKs) including SRC, HCK, FYN, LCK, LYN and YES1.[2] [3]
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.[4] [5] [6] [7] 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.[2] [3]
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.[8] Tyrosine-Kinase CSK is mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.
Mutations
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.[11]
Notes and References
- Web site: Entrez Gene: C-src tyrosine kinase . 2013-07-11 .
- Bergman M, Mustelin T, Oetken C, Partanen J, Flint NA, Amrein KE, Autero M, Burn P, Alitalo K . The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down regulates its catalytic activity . The EMBO Journal . 11 . 8 . 2919–24 . Aug 1992 . 1639064 . 556773 . 10.1002/j.1460-2075.1992.tb05361.x.
- Sun G, Budde RJ . 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 . Sep 1997 . 9281320 . 10.1006/abbi.1997.0236 .
- Nada S, Okada M, MacAuley A, Cooper JA, Nakagawa H . 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 . May 1991 . 1709258 . 10.1038/351069a0 . 1991Natur.351...69N . 4363527 .
- Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H, Ikawa Y, Okada M, Aizawa S . Constitutive activation of Src family kinases in mouse embryos that lack Csk . Cell . 73 . 6 . 1125–35 . Jun 1993 . 8513497 . 10.1016/0092-8674(93)90642-4 . 37988394 .
- Chong YP, Chan AS, Chan KC, Williamson NA, Lerner EC, Smithgall TE, Bjorge JD, Fujita DJ, Purcell AW, Scholz G, Mulhern TD, Cheng HC . 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 . Nov 2006 . 16959780 . 10.1074/jbc.M602951200 . 4281726 . free .
- Chong YP, Mulhern TD, Cheng HC . C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)--endogenous negative regulators of Src-family protein kinases . Growth Factors . 23 . 3 . 233–44 . Sep 2005 . 16243715 . 10.1080/08977190500178877 . 38227036 .
- Bräuninger A, Holtrich U, Strebhardt K, Rübsamen-Waigmann H . Isolation and characterization of a human gene that encodes a new subclass of protein tyrosine kinases . Gene . 110 . 2 . 205–11 . Jan 1992 . 1371489 . 10.1016/0378-1119(92)90649-a.
- Joukov V, Vihinen M, Vainikka S, Sowadski JM, Alitalo K, Bergman M . Identification of csk tyrosine phosphorylation sites and a tyrosine residue important for kinase domain structure . The Biochemical Journal . 322 . 3. 927–35 . Mar 1997 . 9148770 . 1218276 . 10.1042/bj3220927.
- Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skålhegg BS, Hansson V, Mustelin T, Taskén K . 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 . Feb 2001 . 11181701 . 2195911 . 10.1084/jem.193.4.497.
- 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 . Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue . The Journal of Biological Chemistry . 285 . 34 . 26506–18 . Aug 2010 . 20538612 . 2924087 . 10.1074/jbc.M110.111104 . free .
