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Tyrosine-protein kinase CSK
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<h2 id="function">Function</h2> <p>This Non-receptor tyrosine-protein kinase plays an important role in the regulation of <a href="/facts/Cell_growth/wbArMaJU">cell growth</a>, differentiation, <a href="/facts/Cell_migration/5ySAMquQ">migration</a> and <a href="/facts/Immune_response/dtLulqIy">immune response</a>. CSK acts by suppressing the activity of the <a href="/facts/Proto-oncogene_tyrosine-protein_kinase_Src/5SCJqCU4">Src family of protein kinases</a> by <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a> of Src family members at a conserved C-terminal tail site in Src.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a><a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> Upon phosphorylation by other <a href="/facts/Kinases/dhlHpjnD">kinases</a>, Src-family members engage in <a href="/facts/Intramolecular_force/f2Wxm1l3">intramolecular</a> interactions between the <a href="/facts/Phosphotyrosine/RJhEgE4C">phosphotyrosine</a> tail and the <a href="/facts/SH2_domain/1kEmHvzY">SH2 domain</a> 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.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="role-in-development-and-regulation">Role in development and regulation</h2> <p>Tyrosine-protein kinase CSK is involved in the following developmental, metabolic, and <a href="/facts/Signal_transduction/1bs0Me6w">signal transduction</a> cascades: </p><p><a href="/facts/Adherens_junction/CNFe2Qaj">Adherens junction</a> 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 <a href="/facts/Morphogenesis/zHJh8Eae">morphogenesis</a>, regulation of <a href="/facts/Bone_resorption/cMx23mGW">bone resorption</a>, negative regulation of cell proliferation, negative regulation of <a href="/facts/ERK1/TjxAhLGz">ERK1</a> and <a href="/facts/ERK2/VNLaNRdQ">ERK2</a> cascade, negative regulation of <a href="/facts/Golgi_apparatus/F91pGb3t">Golgi</a> to plasma membrane protein transport, negative regulation of <a href="/facts/Interleukin-6/FVQeAWkt">interleukin-6</a> production, negative regulation of kinase activity, negative regulation of <a href="/facts/Low-density_lipoprotein/R5VLPxAg">low-density lipoprotein</a> particle clearance, negative regulation of <a href="/facts/Phagocytosis/eBrv2XKV">phagocytosis</a>, dendrocyte differentiation, peptidyl-tyrosine autophosphorylation, platelet activation, positive regulation of <a href="/facts/MAP_kinase/YdDS5KkU">MAP kinase</a> activity, regulation of cell proliferation, regulation of <a href="/facts/Cytokine/SdWpWABH">cytokine</a> production, regulation of <a href="/facts/Fc_receptor/hpv5q6Hu">Fc receptor</a> mediated stimulatory signaling pathway, <a href="/facts/T_cell/5z6PQ9UN">T cell</a> costimulation, <a href="/facts/T_cell_receptor/zDqyWyG4">T cell receptor</a> signaling pathway.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="expression-and-subcellular-location">Expression and subcellular location</h2> <p>CSK is expressed in the lungs and macrophages as well as several other tissues.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> Tyrosine-Kinase CSK is mainly present in the cytoplasm, but also found in lipid rafts making cell-cell junction.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="mutations">Mutations</h2> <ul><li>Y184F – Abolishes <a href="/facts/Phosphorylation/LXUEEeIL">phosphorylation</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a></li> <li>Y304F – Decreases activity by two-thirds and alters conformation.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></li> <li>S364A – Strong decrease of phosphorylation by <a href="/facts/PRKACA/nRmnLneh">PRKACA</a> (the catalytic subunit of <a href="/facts/Protein_kinase_A/kaKoYfbp">protein kinase A</a>).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a></li></ul> <h2 id="clinical-significance">Clinical significance</h2> <p>Csk's interaction with a phosphatase ("Lyp", gene product of <a href="/facts/PTPN22/uD0HrE1j">PTPN22</a>) is possibly associated with the increased <a href="/facts/Autoimmune_disease/sojBeQ7t">autoimmune diseases</a> associated with <a href="/facts/PTPN22/uD0HrE1j">PTPN22</a> mutations.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=CSK+tyrosine-protein+kinase">CSK tyrosine-protein kinase</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Entrez Gene: C-src tyrosine kinase". Retrieved 2013-07-11. <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=1445" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=1445</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556773" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556773</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>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. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281726" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281726</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556773" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556773</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Universal protein resource accession number P41240 for "Tyrosine-protein kinase CSK" at UniProt. <a href="https://www.uniprot.org/uniprot/P41240" target="_blank">https://www.uniprot.org/uniprot/P41240</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>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. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Universal protein resource accession number P41240 for "Tyrosine-protein kinase CSK" at UniProt. <a href="https://www.uniprot.org/uniprot/P41240" target="_blank">https://www.uniprot.org/uniprot/P41240</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1218276" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1218276</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1218276" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1218276</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195911" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2195911</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924087" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924087</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> </ol>