ID CSK_HUMAN Reviewed; 450 AA. AC P41240; Q2M3N2; Q6FGZ6; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1995, sequence version 1. DT 27-MAR-2024, entry version 241. DE RecName: Full=Tyrosine-protein kinase CSK; DE EC=2.7.10.2 {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:7683130, ECO:0000269|PubMed:9281320}; DE AltName: Full=C-Src kinase; DE AltName: Full=Protein-tyrosine kinase CYL; GN Name=CSK; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PHOSPHORYLATION AT TYR-416. RX PubMed=1945408; RA Partanen J., Armstrong E., Bergman M., Maekelae T.P., Hirvonen H., RA Huebner K., Alitalo K.; RT "CYL encodes a putative cytoplasmic tyrosine kinase lacking the conserved RT tyrosine autophosphorylation site (Y416src)."; RL Oncogene 6:2013-2018(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Lung; RX PubMed=1720539; DOI=10.1073/pnas.88.23.10411; RA Braeuninger A., Holtrich U., Strebhardt K., Ruebsamen-Waigmann H.; RT "Two additional protein-tyrosine kinases expressed in human lung: fourth RT member of the fibroblast growth factor receptor family and an intracellular RT protein-tyrosine kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 88:10411-10415(1991). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY. RX PubMed=1371489; DOI=10.1016/0378-1119(92)90649-a; RA Brauninger A., Holtrich U., Strebhardt K., Rubsamen-Waigmann H.; RT "Isolation and characterization of a human gene that encodes a new subclass RT of protein tyrosine kinases."; RL Gene 110:205-211(1992). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=7683131; RA Braeuninger A., Karn T., Strebhardt K., Ruebsamen-Waigmann H.; RT "Characterization of the human CSK locus."; RL Oncogene 8:1365-1369(1993). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P., RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y., RA LaBaer J.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASP-287; GLN-398 AND RP ARG-442. RG NIEHS SNPs program; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain, and Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION IN PHOSPHORYLATION OF LCK, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=1639064; DOI=10.1002/j.1460-2075.1992.tb05361.x; RA Bergman M., Mustelin T., Oetken C., Partanen J., Flint N.A., Amrein K.E., RA Autero M., Burn P., Alitalo K.; RT "The human p50csk tyrosine kinase phosphorylates p56lck at Tyr-505 and down RT regulates its catalytic activity."; RL EMBO J. 11:2919-2924(1992). RN [9] RP AUTOPHOSPHORYLATION, AND CATALYTIC ACTIVITY. RX PubMed=7683130; RA Bougeret C., Rothhut B., Jullien P., Fischer S., Benarous R.; RT "Recombinant Csk expressed in Escherichia coli is autophosphorylated on RT tyrosine residue(s)."; RL Oncogene 8:1241-1247(1993). RN [10] RP FUNCTION IN PHOSPHORYLATION OF YES1, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=9281320; DOI=10.1006/abbi.1997.0236; RA Sun G., Budde R.J.; RT "Expression, purification, and initial characterization of human Yes RT protein tyrosine kinase from a bacterial expression system."; RL Arch. Biochem. Biophys. 345:135-142(1997). RN [11] RP PHOSPHORYLATION AT TYR-184 AND TYR-304, AND MUTAGENESIS OF TYR-184 AND RP TYR-304. RX PubMed=9148770; DOI=10.1042/bj3220927; RA Joukov V., Vihinen M., Vainikka S., Sowadski J.M., Alitalo K., Bergman M.; RT "Identification of csk tyrosine phosphorylation sites and a tyrosine RT residue important for kinase domain structure."; RL Biochem. J. 322:927-935(1997). RN [12] RP INTERACTION WITH TGFB1I1. RX PubMed=10838081; DOI=10.1016/s0014-5793(00)01597-0; RA Ishino M., Aoto H., Sasaski H., Suzuki R., Sasaki T.; RT "Phosphorylation of Hic-5 at tyrosine 60 by CAKbeta and Fyn."; RL FEBS Lett. 474:179-183(2000). RN [13] RP INTERACTION WITH PAG1. RX PubMed=10790433; DOI=10.1084/jem.191.9.1591; RA Brdicka T., Pavlistova D., Bruyns E., Leo A., Korinek V., Angelisova P., RA Scherer J., Shevchenko A., Shevchenko A., Hilgert I., Cerny J., Drbal K., RA Kuramitsu Y., Horejsi V., Schraven B.; RT "Phosphoprotein associated with glycosphingolipid-enriched microdomains RT (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds RT the protein tyrosine kinase csk and is involved in regulation of T cell RT activation."; RL J. Exp. Med. 191:1591-1604(2000). RN [14] RP INTERACTION WITH SIT1. RX PubMed=11433379; RX DOI=10.1002/1521-4141(200106)31:6<1825::aid-immu1825>3.0.co;2-v; RA Pfrepper K.-I., Marie-Cardine A., Simeoni L., Kuramitsu Y., Leo A., RA Spicka J., Hilgert I., Scherer J., Schraven B.; RT "Structural and functional dissection of the cytoplasmic domain of the RT transmembrane adaptor protein SIT (SHP2-interacting transmembrane adaptor RT protein)."; RL Eur. J. Immunol. 31:1825-1836(2001). RN [15] RP PHOSPHORYLATION AT SER-364 BY PKA, AND MUTAGENESIS OF SER-364. RX PubMed=11181701; DOI=10.1084/jem.193.4.497; RA Vang T., Torgersen K.M., Sundvold V., Saxena M., Levy F.O., Skalhegg B.S., RA Hansson V., Mustelin T., Tasken K.; RT "Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein RT kinase inhibits signaling through the T cell receptor."; RL J. Exp. Med. 193:497-507(2001). RN [16] RP INTERACTION WITH LIME1. RX PubMed=14610046; DOI=10.1084/jem.20031484; RA Brdickova N., Brdicka T., Angelisova P., Horvath O., Spicka J., Hilgert I., RA Paces J., Simeoni L., Kliche S., Merten C., Schraven B., Horejsi V.; RT "LIME: a new membrane raft-associated adaptor protein involved in CD4 and RT CD8 coreceptor signaling."; RL J. Exp. Med. 198:1453-1462(2003). RN [17] RP INTERACTION WITH PTPN22. RX PubMed=15208781; DOI=10.1086/422827; RA Begovich A.B., Carlton V.E., Honigberg L.A., Schrodi S.J., RA Chokkalingam A.P., Alexander H.C., Ardlie K.G., Huang Q., Smith A.M., RA Spoerke J.M., Conn M.T., Chang M., Chang S.Y., Saiki R.K., Catanese J.J., RA Leong D.U., Garcia V.E., McAllister L.B., Jeffery D.A., Lee A.T., RA Batliwalla F., Remmers E., Criswell L.A., Seldin M.F., Kastner D.L., RA Amos C.I., Sninsky J.J., Gregersen P.K.; RT "A missense single-nucleotide polymorphism in a gene encoding a protein RT tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis."; RL Am. J. Hum. Genet. 75:330-337(2004). RN [18] RP REVIEW. RX PubMed=16243715; DOI=10.1080/08977190500178877; RA Chong Y.P., Mulhern T.D., Cheng H.C.; RT "C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) -- endogenous RT negative regulators of Src-family protein kinases."; RL Growth Factors 23:233-244(2005). RN [19] RP INTERACTION WITH SRCIN1. RX PubMed=17525734; DOI=10.1038/sj.emboj.7601724; RA Di Stefano P., Damiano L., Cabodi S., Aramu S., Tordella L., Praduroux A., RA Piva R., Cavallo F., Forni G., Silengo L., Tarone G., Turco E., RA Defilippi P.; RT "p140Cap protein suppresses tumour cell properties, regulating Csk and Src RT kinase activity."; RL EMBO J. 26:2843-2855(2007). RN [20] RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [21] RP HOMODIMERIZATION. RX PubMed=19888460; DOI=10.1371/journal.pone.0007683; RA Levinson N.M., Visperas P.R., Kuriyan J.; RT "The tyrosine kinase Csk dimerizes through Its SH3 domain."; RL PLoS ONE 4:E7683-E7683(2009). RN [22] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [23] RP INTERACTION WITH RHOH. RX PubMed=20851766; DOI=10.1016/j.cellsig.2010.09.009; RA Wang H., Zeng X., Fan Z., Lim B.; RT "RhoH modulates pre-TCR and TCR signalling by regulating LCK."; RL Cell. Signal. 23:249-258(2011). RN [24] RP INTERACTION WITH SCIMP. RX PubMed=21930792; DOI=10.1128/mcb.05817-11; RA Draber P., Vonkova I., Stepanek O., Hrdinka M., Kucova M., Skopcova T., RA Otahal P., Angelisova P., Horejsi V., Yeung M., Weiss A., Brdicka T.; RT "SCIMP, a transmembrane adapter protein involved in major RT histocompatibility complex class II signaling."; RL Mol. Cell. Biol. 31:4550-4562(2011). RN [25] RP INTERACTION WITH LRRK1. RX PubMed=23526378; DOI=10.1002/jbmr.1935; RA Xing W., Liu J., Cheng S., Vogel P., Mohan S., Brommage R.; RT "Targeted disruption of leucine-rich repeat kinase 1 but not leucine-rich RT repeat kinase 2 in mice causes severe osteopetrosis."; RL J. Bone Miner. Res. 28:1962-1974(2013). RN [26] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-71. RX PubMed=7511113; DOI=10.1016/0014-5793(94)80244-0; RA Borchert T.V., Mathieu M., Zeelen J.P., Courtneidge S.A., Wierenga R.K.; RT "The crystal structure of human CskSH3: structural diversity near the RT- RT Src and n-Src loop."; RL FEBS Lett. 341:79-85(1994). RN [27] RP VARIANT [LARGE SCALE ANALYSIS] LEU-45. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Non-receptor tyrosine-protein kinase that plays an important CC role in the regulation of cell growth, differentiation, migration and CC immune response. Phosphorylates tyrosine residues located in the C- CC terminal tails of Src-family kinases (SFKs) including LCK, SRC, HCK, CC FYN, LYN, CSK or YES1. Upon tail phosphorylation, Src-family members CC engage in intramolecular interactions between the phosphotyrosine tail CC and the SH2 domain that result in an inactive conformation. To inhibit CC SFKs, CSK is recruited to the plasma membrane via binding to CC transmembrane proteins or adapter proteins located near the plasma CC membrane. Suppresses signaling by various surface receptors, including CC T-cell receptor (TCR) and B-cell receptor (BCR) by phosphorylating and CC maintaining inactive several positive effectors such as FYN or LCK. CC {ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:9281320}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; CC Evidence={ECO:0000269|PubMed:1639064, ECO:0000269|PubMed:7683130, CC ECO:0000269|PubMed:9281320}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:9281320}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:1639064}; CC -!- SUBUNIT: Homodimer (via SH3-domain) (PubMed:19888460). Interacts with CC PTPN22 (PubMed:15208781). Interacts with phosphorylated SIT1, PAG1, CC LIME1 and TGFB1I1; these interactions serve to recruit CSK to the CC membrane where it can phosphorylate and inhibit Src-family kinases CC (PubMed:11433379, PubMed:10790433, PubMed:14610046, PubMed:10838081). CC Interacts with SRCIN1 (PubMed:17525734). Interacts with RHOH CC (PubMed:20851766). Interacts (via SH2 domain) with SCIMP; this CC interaction is dependent on phosphorylation of SCIMP 'Tyr-107' CC (PubMed:21930792). Interacts (via SH2 domain) with PRAG1 (when CC phosphorylated at 'Tyr-391'); this interaction prevents translocation CC of CSK from the cytoplasm to the membrane leading to increased activity CC of CSK (By similarity). Interacts with LRRK1 (PubMed:23526378). CC {ECO:0000250|UniProtKB:P32577, ECO:0000269|PubMed:10790433, CC ECO:0000269|PubMed:10838081, ECO:0000269|PubMed:11433379, CC ECO:0000269|PubMed:14610046, ECO:0000269|PubMed:15208781, CC ECO:0000269|PubMed:17525734, ECO:0000269|PubMed:20851766, CC ECO:0000269|PubMed:21930792, ECO:0000269|PubMed:23526378}. CC -!- INTERACTION: CC P41240; P41240: CSK; NbExp=7; IntAct=EBI-1380630, EBI-1380630; CC P41240; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-1380630, EBI-742054; CC P41240; P08069: IGF1R; NbExp=5; IntAct=EBI-1380630, EBI-475981; CC P41240; Q5T7N3: KANK4; NbExp=3; IntAct=EBI-1380630, EBI-9355810; CC P41240; Q9NWQ8: PAG1; NbExp=5; IntAct=EBI-1380630, EBI-2828115; CC P41240; P08575: PTPRC; NbExp=3; IntAct=EBI-1380630, EBI-1341; CC P41240; P49023: PXN; NbExp=4; IntAct=EBI-1380630, EBI-702209; CC P41240; Q6UWF3: SCIMP; NbExp=3; IntAct=EBI-1380630, EBI-2872510; CC P41240; Q7VLE8: lspA1; Xeno; NbExp=4; IntAct=EBI-1380630, EBI-26445163; CC P41240; P00523: SRC; Xeno; NbExp=7; IntAct=EBI-1380630, EBI-848039; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Cell membrane CC {ECO:0000250}. Note=Mainly cytoplasmic, also present in lipid rafts. CC {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Expressed in lung and macrophages. CC {ECO:0000269|PubMed:1371489}. CC -!- DOMAIN: The architecture of this protein is similar to that of Src- CC family kinases (SFKs) with one N-terminal SH3 domain, one SH2 domain, CC and a C-terminal kinase domain. CC -!- PTM: Phosphorylated at Ser-364 by PKA, leading to increased activity. CC Autophosphorylated. {ECO:0000269|PubMed:11181701, CC ECO:0000269|PubMed:9148770}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. CSK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/csk/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X60114; CAA42713.1; -; mRNA. DR EMBL; X59932; CAA42556.1; -; mRNA. DR EMBL; X74765; CAB58562.1; -; Genomic_DNA. DR EMBL; CR541960; CAG46758.1; -; mRNA. DR EMBL; DQ075211; AAY57329.1; -; Genomic_DNA. DR EMBL; BC104847; AAI04848.1; -; mRNA. DR EMBL; BC104875; AAI04876.1; -; mRNA. DR EMBL; BC106073; AAI06074.1; -; mRNA. DR CCDS; CCDS10269.1; -. DR PIR; JH0559; JH0559. DR RefSeq; NP_001120662.1; NM_001127190.1. DR RefSeq; NP_004374.1; NM_004383.2. DR RefSeq; XP_005254222.1; XM_005254165.4. DR RefSeq; XP_016877414.1; XM_017021925.1. DR PDB; 1BYG; X-ray; 2.40 A; A=173-450. DR PDB; 1CSK; X-ray; 2.50 A; A/B/C/D=1-71. DR PDB; 3D7T; X-ray; 2.90 A; A=188-450. DR PDB; 3D7U; X-ray; 4.11 A; A/C=188-450. DR PDB; 3EAC; X-ray; 1.37 A; A=73-178. DR PDB; 3EAZ; X-ray; 1.31 A; A=73-178. DR PDBsum; 1BYG; -. DR PDBsum; 1CSK; -. DR PDBsum; 3D7T; -. DR PDBsum; 3D7U; -. DR PDBsum; 3EAC; -. DR PDBsum; 3EAZ; -. DR AlphaFoldDB; P41240; -. DR BMRB; P41240; -. DR SMR; P41240; -. DR BioGRID; 107832; 848. DR ELM; P41240; -. DR IntAct; P41240; 93. DR MINT; P41240; -. DR STRING; 9606.ENSP00000220003; -. DR BindingDB; P41240; -. DR ChEMBL; CHEMBL2634; -. DR DrugBank; DB01254; Dasatinib. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB02010; Staurosporine. DR DrugBank; DB05075; TG-100801. DR DrugCentral; P41240; -. DR GuidetoPHARMACOLOGY; 1994; -. DR GlyGen; P41240; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P41240; -. DR MetOSite; P41240; -. DR PhosphoSitePlus; P41240; -. DR BioMuta; CSK; -. DR DMDM; 729887; -. DR OGP; P41240; -. DR CPTAC; CPTAC-2824; -. DR EPD; P41240; -. DR jPOST; P41240; -. DR MassIVE; P41240; -. DR MaxQB; P41240; -. DR PaxDb; 9606-ENSP00000220003; -. DR PeptideAtlas; P41240; -. DR ProteomicsDB; 55450; -. DR Pumba; P41240; -. DR Antibodypedia; 4405; 882 antibodies from 42 providers. DR DNASU; 1445; -. DR Ensembl; ENST00000220003.14; ENSP00000220003.9; ENSG00000103653.17. DR Ensembl; ENST00000439220.6; ENSP00000414764.2; ENSG00000103653.17. DR Ensembl; ENST00000567571.5; ENSP00000454906.1; ENSG00000103653.17. DR GeneID; 1445; -. DR KEGG; hsa:1445; -. DR MANE-Select; ENST00000220003.14; ENSP00000220003.9; NM_004383.3; NP_004374.1. DR UCSC; uc002ays.3; human. DR AGR; HGNC:2444; -. DR DisGeNET; 1445; -. DR GeneCards; CSK; -. DR HGNC; HGNC:2444; CSK. DR HPA; ENSG00000103653; Tissue enhanced (lymphoid). DR MIM; 124095; gene. DR neXtProt; NX_P41240; -. DR OpenTargets; ENSG00000103653; -. DR PharmGKB; PA26946; -. DR VEuPathDB; HostDB:ENSG00000103653; -. DR eggNOG; KOG0197; Eukaryota. DR GeneTree; ENSGT00940000157431; -. DR HOGENOM; CLU_000288_7_2_1; -. DR InParanoid; P41240; -. DR OMA; PTMTTHS; -. DR OrthoDB; 1614410at2759; -. DR PhylomeDB; P41240; -. DR TreeFam; TF351634; -. DR BRENDA; 2.7.10.2; 2681. DR PathwayCommons; P41240; -. DR Reactome; R-HSA-180292; GAB1 signalosome. DR Reactome; R-HSA-202427; Phosphorylation of CD3 and TCR zeta chains. DR Reactome; R-HSA-354192; Integrin signaling. DR Reactome; R-HSA-389948; PD-1 signaling. DR Reactome; R-HSA-5674135; MAP2K and MAPK activation. DR Reactome; R-HSA-6802946; Signaling by moderate kinase activity BRAF mutants. DR Reactome; R-HSA-6802948; Signaling by high-kinase activity BRAF mutants. DR Reactome; R-HSA-6802952; Signaling by BRAF and RAF1 fusions. DR Reactome; R-HSA-6802955; Paradoxical activation of RAF signaling by kinase inactive BRAF. DR Reactome; R-HSA-9013407; RHOH GTPase cycle. DR Reactome; R-HSA-9649948; Signaling downstream of RAS mutants. DR Reactome; R-HSA-9656223; Signaling by RAF1 mutants. DR Reactome; R-HSA-9706369; Negative regulation of FLT3. DR SignaLink; P41240; -. DR SIGNOR; P41240; -. DR BioGRID-ORCS; 1445; 85 hits in 1203 CRISPR screens. DR ChiTaRS; CSK; human. DR EvolutionaryTrace; P41240; -. DR GeneWiki; C-src_tyrosine_kinase; -. DR GenomeRNAi; 1445; -. DR Pharos; P41240; Tchem. DR PRO; PR:P41240; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P41240; Protein. DR Bgee; ENSG00000103653; Expressed in granulocyte and 189 other cell types or tissues. DR ExpressionAtlas; P41240; baseline and differential. DR GO; GO:0005911; C:cell-cell junction; IEA:Ensembl. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IPI:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IBA:GO_Central. DR GO; GO:0070064; F:proline-rich region binding; IEA:Ensembl. DR GO; GO:0034236; F:protein kinase A catalytic subunit binding; IPI:UniProtKB. DR GO; GO:0019903; F:protein phosphatase binding; IEA:Ensembl. DR GO; GO:0004713; F:protein tyrosine kinase activity; TAS:Reactome. DR GO; GO:1990782; F:protein tyrosine kinase binding; IEA:Ensembl. DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW. DR GO; GO:0034332; P:adherens junction organization; IBA:GO_Central. DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl. DR GO; GO:0045779; P:negative regulation of bone resorption; IEA:Ensembl. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0042997; P:negative regulation of Golgi to plasma membrane protein transport; IDA:UniProtKB. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl. DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IEA:Ensembl. DR GO; GO:0050765; P:negative regulation of phagocytosis; IEA:Ensembl. DR GO; GO:0048709; P:oligodendrocyte differentiation; IEA:Ensembl. DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc. DR GO; GO:0060368; P:regulation of Fc receptor mediated stimulatory signaling pathway; IBA:GO_Central. DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome. DR GO; GO:0050852; P:T cell receptor signaling pathway; TAS:Reactome. DR CDD; cd05082; PTKc_Csk; 1. DR CDD; cd09937; SH2_csk_like; 1. DR CDD; cd11769; SH3_CSK; 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR Gene3D; 2.30.30.40; SH3 Domains; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR035027; Csk-like_SH2. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR036860; SH2_dom_sf. DR InterPro; IPR036028; SH3-like_dom_sf. DR InterPro; IPR001452; SH3_domain. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR PANTHER; PTHR24418; TYROSINE-PROTEIN KINASE; 1. DR PANTHER; PTHR24418:SF407; TYROSINE-PROTEIN KINASE CSK; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR Pfam; PF00017; SH2; 1. DR Pfam; PF00018; SH3_1; 1. DR PRINTS; PR00401; SH2DOMAIN. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00252; SH2; 1. DR SMART; SM00326; SH3; 1. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR SUPFAM; SSF50044; SH3-domain; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; PS50001; SH2; 1. DR PROSITE; PS50002; SH3; 1. DR Genevisible; P41240; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Adaptive immunity; ATP-binding; Cell membrane; KW Cytoplasm; Immunity; Kinase; Magnesium; Manganese; Membrane; Metal-binding; KW Nucleotide-binding; Phosphoprotein; Reference proteome; SH2 domain; KW SH3 domain; Transferase; Tyrosine-protein kinase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0007744|PubMed:19413330" FT CHAIN 2..450 FT /note="Tyrosine-protein kinase CSK" FT /id="PRO_0000088070" FT DOMAIN 9..70 FT /note="SH3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192" FT DOMAIN 82..171 FT /note="SH2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191" FT DOMAIN 195..449 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 9..70 FT /note="Interaction with PTPN22" FT /evidence="ECO:0000250|UniProtKB:P41241" FT ACT_SITE 314 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10028" FT BINDING 201..209 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 222 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0007744|PubMed:19413330" FT MOD_RES 184 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:9148770" FT MOD_RES 304 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:9148770" FT MOD_RES 364 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000269|PubMed:11181701" FT MOD_RES 416 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:1945408" FT VARIANT 45 FT /note="P -> L" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_041678" FT VARIANT 287 FT /note="G -> D (in dbSNP:rs34866753)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_025203" FT VARIANT 398 FT /note="R -> Q (in dbSNP:rs34616395)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_025204" FT VARIANT 442 FT /note="H -> R (in dbSNP:rs35556162)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_025205" FT MUTAGEN 184 FT /note="Y->F: Abolishes phosphorylation." FT /evidence="ECO:0000269|PubMed:9148770" FT MUTAGEN 304 FT /note="Y->F: Decreases activity by two-thirds and alters FT conformation." FT /evidence="ECO:0000269|PubMed:9148770" FT MUTAGEN 364 FT /note="S->A: Strong decrease of phosphorylation by PRKACA FT (catalytic subunit of PKA)." FT /evidence="ECO:0000269|PubMed:11181701" FT STRAND 12..18 FT /evidence="ECO:0007829|PDB:1CSK" FT STRAND 35..41 FT /evidence="ECO:0007829|PDB:1CSK" FT STRAND 47..51 FT /evidence="ECO:0007829|PDB:1CSK" FT STRAND 57..61 FT /evidence="ECO:0007829|PDB:1CSK" FT STRAND 64..66 FT /evidence="ECO:0007829|PDB:1CSK" FT HELIX 77..79 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 83..86 FT /evidence="ECO:0007829|PDB:3EAC" FT HELIX 89..95 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 103..108 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 116..122 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 125..130 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 137..144 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 146..148 FT /evidence="ECO:0007829|PDB:3EAZ" FT HELIX 149..158 FT /evidence="ECO:0007829|PDB:3EAZ" FT STRAND 163..165 FT /evidence="ECO:0007829|PDB:3EAZ" FT HELIX 192..194 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 195..203 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 208..214 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 217..223 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 231..235 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 237..240 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 251..255 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 263..266 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 274..285 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 288..307 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 317..319 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 320..322 FT /evidence="ECO:0007829|PDB:1BYG" FT STRAND 328..330 FT /evidence="ECO:0007829|PDB:1BYG" FT TURN 350..352 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 355..360 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 365..380 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 392..394 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 395..399 FT /evidence="ECO:0007829|PDB:1BYG" FT TURN 400..402 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 413..422 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 427..429 FT /evidence="ECO:0007829|PDB:1BYG" FT HELIX 433..446 FT /evidence="ECO:0007829|PDB:1BYG" SQ SEQUENCE 450 AA; 50704 MW; 431023A88C54E00C CRC64; MSAIQAAWPS GTECIAKYNF HGTAEQDLPF CKGDVLTIVA VTKDPNWYKA KNKVGREGII PANYVQKREG VKAGTKLSLM PWFHGKITRE QAERLLYPPE TGLFLVREST NYPGDYTLCV SCDGKVEHYR IMYHASKLSI DEEVYFENLM QLVEHYTSDA DGLCTRLIKP KVMEGTVAAQ DEFYRSGWAL NMKELKLLQT IGKGEFGDVM LGDYRGNKVA VKCIKNDATA QAFLAEASVM TQLRHSNLVQ LLGVIVEEKG GLYIVTEYMA KGSLVDYLRS RGRSVLGGDC LLKFSLDVCE AMEYLEGNNF VHRDLAARNV LVSEDNVAKV SDFGLTKEAS STQDTGKLPV KWTAPEALRE KKFSTKSDVW SFGILLWEIY SFGRVPYPRI PLKDVVPRVE KGYKMDAPDG CPPAVYEVMK NCWHLDAAMR PSFLQLREQL EHIKTHELHL //