CSK_RAT
ID CSK_RAT Reviewed; 450 AA.
AC P32577; Q4G003;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1993, sequence version 1.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Tyrosine-protein kinase CSK;
DE EC=2.7.10.2 {ECO:0000269|PubMed:1722201, ECO:0000269|PubMed:21873224};
DE AltName: Full=C-Src kinase;
GN Name=Csk;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=1709258; DOI=10.1038/351069a0;
RA Nada S., Okada M., McAuley A., Cooper J.A., Nakagawa H.;
RT "Cloning of a complementary DNA for a protein-tyrosine kinase that
RT specifically phosphorylates a negative regulatory site of p60c-src.";
RL Nature 351:69-72(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thymus;
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 [3]
RP FUNCTION IN PHOSPHORYLATION OF LYN AND FYN, CATALYTIC ACTIVITY, AND
RP COFACTOR.
RX PubMed=1722201; DOI=10.1016/s0021-9258(18)54220-4;
RA Okada M., Nada S., Yamanashi Y., Yamamoto T., Nakagawa H.;
RT "CSK: a protein-tyrosine kinase involved in regulation of src family
RT kinases.";
RL J. Biol. Chem. 266:24249-24252(1991).
RN [4]
RP FUNCTION IN PHOSPHORYLATION OF FGR.
RX PubMed=7515063; DOI=10.1016/s0021-9258(17)40763-0;
RA Ruzzene M., James P., Brunati A.M., Donella-Deana A., Pinna L.A.;
RT "Regulation of c-Fgr protein kinase by c-Src kinase (CSK) and by
RT polycationic effectors.";
RL J. Biol. Chem. 269:15885-15891(1994).
RN [5]
RP INTERACTION WITH PAG1.
RX PubMed=10801129; DOI=10.1038/35010121;
RA Kawabuchi M., Satomi Y., Takao T., Shimonishi Y., Nada S., Nagai K.,
RA Tarakhovsky A., Okada M.;
RT "Transmembrane phosphoprotein Cbp regulates the activities of Src-family
RT tyrosine kinases.";
RL Nature 404:999-1003(2000).
RN [6]
RP INTERACTION WITH PAG1.
RX PubMed=14613929; DOI=10.1074/jbc.m311278200;
RA Matsuoka H., Nada S., Okada M.;
RT "Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases
RT in epidermal growth factor signaling.";
RL J. Biol. Chem. 279:5975-5983(2004).
RN [7]
RP SUBCELLULAR LOCATION, INTERACTION WITH PRAG1, AND FUNCTION IN
RP PHOSPHORYLATION OF PRAG1.
RX PubMed=21873224; DOI=10.1073/pnas.1107740108;
RA Safari F., Murata-Kamiya N., Saito Y., Hatakeyama M.;
RT "Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala
RT (EPIYA) motif that is exploited by bacterial effectors.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14938-14943(2011).
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 (By
CC similarity). {ECO:0000250, ECO:0000269|PubMed:1722201,
CC ECO:0000269|PubMed:21873224, ECO:0000269|PubMed:7515063}.
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:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:1722201, ECO:0000269|PubMed:21873224};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:1722201};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P41240};
CC -!- SUBUNIT: Homodimer (via SH3-domain). Interacts with PTPN22. Interacts
CC with phosphorylated SIT1, PAG1, LIME1 and TGFB1I1; these interactions
CC serve to recruit CSK to the membrane where it can phosphorylate and
CC inhibit Src-family kinases. Interacts with SRCIN1. Interacts with RHOH.
CC Interacts (via SH2 domain) with SCIMP; this interaction is dependent on
CC phosphorylation of SCIMP 'Tyr-96' (By similarity). Interacts (via SH2
CC domain) with PRAG1 (when phosphorylated at 'Tyr-391'); this interaction
CC prevents translocation of CSK from the cytoplasm to the membrane
CC leading to increased activity of CSK (PubMed:21873224).
CC {ECO:0000250|UniProtKB:P41240, ECO:0000250|UniProtKB:P41241,
CC ECO:0000269|PubMed:21873224}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21873224}. Cell
CC membrane {ECO:0000250}. Note=Mainly cytoplasmic, also present in lipid
CC rafts. {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Enriched in lymphoid tissues.
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. {ECO:0000250}.
CC -!- PTM: Phosphorylated at Ser-364 by PKA, leading to increased activity.
CC Autophosphorylated (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; X58631; CAA41484.1; -; mRNA.
DR EMBL; BC098863; AAH98863.1; -; mRNA.
DR PIR; S15094; S15094.
DR RefSeq; NP_001025210.1; NM_001030039.1.
DR RefSeq; XP_006243225.1; XM_006243163.1.
DR RefSeq; XP_006243226.1; XM_006243164.3.
DR PDB; 1K9A; X-ray; 2.50 A; A/B/C/D/E/F=1-450.
DR PDB; 2RSY; NMR; -; A=80-173.
DR PDBsum; 1K9A; -.
DR PDBsum; 2RSY; -.
DR AlphaFoldDB; P32577; -.
DR BMRB; P32577; -.
DR SMR; P32577; -.
DR BioGRID; 261119; 6.
DR ELM; P32577; -.
DR IntAct; P32577; 20.
DR MINT; P32577; -.
DR STRING; 10116.ENSRNOP00000026358; -.
DR BindingDB; P32577; -.
DR ChEMBL; CHEMBL4365; -.
DR iPTMnet; P32577; -.
DR PhosphoSitePlus; P32577; -.
DR jPOST; P32577; -.
DR PaxDb; P32577; -.
DR Ensembl; ENSRNOT00000026358; ENSRNOP00000026358; ENSRNOG00000019374.
DR GeneID; 315707; -.
DR KEGG; rno:315707; -.
DR UCSC; RGD:1308800; rat.
DR CTD; 1445; -.
DR RGD; 1308800; Csk.
DR eggNOG; KOG0197; Eukaryota.
DR GeneTree; ENSGT00940000157431; -.
DR HOGENOM; CLU_000288_7_2_1; -.
DR InParanoid; P32577; -.
DR OMA; QTMPWFH; -.
DR OrthoDB; 491765at2759; -.
DR PhylomeDB; P32577; -.
DR TreeFam; TF351634; -.
DR BRENDA; 2.7.10.2; 5301.
DR Reactome; R-RNO-180292; GAB1 signalosome.
DR Reactome; R-RNO-202427; Phosphorylation of CD3 and TCR zeta chains.
DR Reactome; R-RNO-354192; Integrin signaling.
DR Reactome; R-RNO-389948; PD-1 signaling.
DR Reactome; R-RNO-5674135; MAP2K and MAPK activation.
DR Reactome; R-RNO-9013407; RHOH GTPase cycle.
DR Reactome; R-RNO-9706369; Negative regulation of FLT3.
DR EvolutionaryTrace; P32577; -.
DR PRO; PR:P32577; -.
DR Proteomes; UP000002494; Chromosome 8.
DR Bgee; ENSRNOG00000019374; Expressed in spleen and 18 other tissues.
DR Genevisible; P32577; RN.
DR GO; GO:0005911; C:cell-cell junction; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
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; IPI:BHF-UCL.
DR GO; GO:0034236; F:protein kinase A catalytic subunit binding; ISO:RGD.
DR GO; GO:0019903; F:protein phosphatase binding; IPI:BHF-UCL.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:RGD.
DR GO; GO:1990782; F:protein tyrosine kinase binding; IPI:RGD.
DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR GO; GO:0034332; P:adherens junction organization; IEP:RGD.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:0071375; P:cellular response to peptide hormone stimulus; IDA:RGD.
DR GO; GO:0045779; P:negative regulation of bone resorption; IDA:RGD.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:RGD.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:RGD.
DR GO; GO:0042997; P:negative regulation of Golgi to plasma membrane protein transport; ISO:RGD.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:RGD.
DR GO; GO:0033673; P:negative regulation of kinase activity; IDA:RGD.
DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IDA:RGD.
DR GO; GO:0050765; P:negative regulation of phagocytosis; IDA:RGD.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEP:RGD.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:RGD.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0060368; P:regulation of Fc receptor mediated stimulatory signaling pathway; IDA:RGD.
DR CDD; cd09937; SH2_csk_like; 1.
DR Gene3D; 3.30.505.10; -; 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 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; SSF50044; SSF50044; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR SUPFAM; SSF56112; SSF56112; 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.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; ATP-binding; Cell membrane;
KW Cytoplasm; Direct protein sequencing; Immunity; Kinase; Magnesium;
KW Manganese; Membrane; Metal-binding; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; SH2 domain; SH3 domain; Transferase;
KW Tyrosine-protein kinase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P41240"
FT CHAIN 2..450
FT /note="Tyrosine-protein kinase CSK"
FT /id="PRO_0000088072"
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..445
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:P41240"
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:0000250|UniProtKB:P41240"
FT MOD_RES 184
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P41240"
FT MOD_RES 304
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P41240"
FT MOD_RES 364
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:P41240"
FT MOD_RES 416
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P41240"
FT STRAND 13..18
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 23..27
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 35..41
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 47..51
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 57..61
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 89..95
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 103..108
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 110..112
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 115..121
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 123..134
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 137..144
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 146..148
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 149..158
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 163..165
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 179..185
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 192..194
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 195..203
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 205..214
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 217..226
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 231..241
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 251..256
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 262..267
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 274..281
FT /evidence="ECO:0007829|PDB:1K9A"
FT TURN 283..285
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 288..307
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 317..319
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 320..322
FT /evidence="ECO:0007829|PDB:1K9A"
FT STRAND 328..330
FT /evidence="ECO:0007829|PDB:1K9A"
FT TURN 350..352
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 355..359
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 365..380
FT /evidence="ECO:0007829|PDB:1K9A"
FT TURN 381..383
FT /evidence="ECO:0007829|PDB:1K9A"
FT TURN 392..394
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 395..400
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 413..422
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 427..429
FT /evidence="ECO:0007829|PDB:1K9A"
FT HELIX 433..445
FT /evidence="ECO:0007829|PDB:1K9A"
FT TURN 446..449
FT /evidence="ECO:0007829|PDB:1K9A"
SQ SEQUENCE 450 AA; 50746 MW; 393DC8D737DAC67A CRC64;
MSAIQASWPS GTECIAKYNF HGTAEQDLPF CKGDVLTIVA VTKDPNWYKA KNKVGREGII
PANYVQKREG VKAGTKLSLM PWFHGKITRE QAERLLYPPE TGLFLVREST NYPGDYTLCV
SCEGKVEHYR IMYHASKLSI DEEVYFENLM QLVEHYTTDA 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 CPPAVYDVMK
NCWHLDAATR PTFLQLREQL EHIRTHELHL
