Biology:Tyrosine-protein kinase CSK

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Short description: Kinase enzyme that phosphorylates Src-family kinases
This article is about the kinase CSK, for the kinase that is phosphorylated by CSK, see c-Src.
A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[8]

Expression and subcellular location

CSK is expressed in the lungs and macrophages as well as several other tissues.[9] Tyrosine-Kinase CSK is mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.[8]

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.[12]

References

  1. ↑ "Entrez Gene: C-src tyrosine kinase". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=1445. 
  2. ↑ 2.0 2.1 "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. doi:10.1002/j.1460-2075.1992.tb05361.x. PMID 1639064. 
  3. ↑ 3.0 3.1 "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. doi:10.1006/abbi.1997.0236. PMID 9281320. 
  4. ↑ "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. doi:10.1038/351069a0. PMID 1709258. Bibcode: 1991Natur.351...69N. 
  5. ↑ "Constitutive activation of Src family kinases in mouse embryos that lack Csk". Cell 73 (6): 1125–35. Jun 1993. doi:10.1016/0092-8674(93)90642-4. PMID 8513497. 
  6. ↑ "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. doi:10.1074/jbc.M602951200. PMID 16959780. 
  7. ↑ "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. doi:10.1080/08977190500178877. PMID 16243715. 
  8. ↑ 8.0 8.1 Universal protein resource accession number P41240 for "Tyrosine-protein kinase CSK" at UniProt.
  9. ↑ "Isolation and characterization of a human gene that encodes a new subclass of protein tyrosine kinases". Gene 110 (2): 205–11. Jan 1992. doi:10.1016/0378-1119(92)90649-a. PMID 1371489. 
  10. ↑ 10.0 10.1 "Identification of csk tyrosine phosphorylation sites and a tyrosine residue important for kinase domain structure". The Biochemical Journal 322 (3): 927–35. Mar 1997. doi:10.1042/bj3220927. PMID 9148770. 
  11. ↑ "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. doi:10.1084/jem.193.4.497. PMID 11181701. 
  12. ↑ "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. doi:10.1074/jbc.M110.111104. PMID 20538612. 

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