CRK_RAT
ID CRK_RAT Reviewed; 304 AA.
AC Q63768;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Adapter molecule crk;
DE AltName: Full=Proto-oncogene c-Crk;
DE AltName: Full=p38;
GN Name=Crk; Synonyms=Crko;
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].
RC TISSUE=Kidney;
RX PubMed=8901553; DOI=10.1073/pnas.93.22.12177;
RA Kizaka-Kondoh S., Matsuda M., Okayama H.;
RT "CrkII signals from epidermal growth factor receptor to Ras.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:12177-12182(1996).
RN [2]
RP PHOSPHORYLATION AT TYR-221, AND MUTAGENESIS OF TYR-221.
RX PubMed=12198159; DOI=10.1093/emboj/cdf446;
RA Abassi Y.A., Vuori K.;
RT "Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of
RT Crk and Rac and activation of Rac signaling.";
RL EMBO J. 21:4571-4582(2002).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Involved in cell branching and adhesion mediated by BCAR1-
CC CRK-RAPGEF1 signaling and activation of RAP1.
CC {ECO:0000250|UniProtKB:P46108}.
CC -!- FUNCTION: [Isoform Crk-II]: Regulates cell adhesion, spreading and
CC migration. Mediates attachment-induced MAPK8 activation, membrane
CC ruffling and cell motility in a Rac-dependent manner. Involved in
CC phagocytosis of apoptotic cells and cell motility via its interaction
CC with DOCK1 and DOCK4 (By similarity). May regulate the EFNA5-EPHA3
CC signaling (By similarity). {ECO:0000250|UniProtKB:P46108,
CC ECO:0000250|UniProtKB:Q64010}.
CC -!- SUBUNIT: Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK
CC (By similarity). Within the complex, interacts with SH2D3C (via C-
CC terminus), and BCAR1/CAS (By similarity). Found in a complex with ABL1,
CC ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation
CC by ABL kinases (By similarity). Interacts with ABL1, C3G, DOCK3, DOCK5,
CC MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2
CC domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced
CC tyrosine phosphorylation. Interacts (via SH2 domain) with several
CC tyrosine-phosphorylated growth factor receptors such as EGFR and INSR.
CC Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and
CC DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG.
CC Isoform Crk-II interacts with KIT. Interacts with EPHA3; upon
CC activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase
CC activity-dependent. Interacts with EPHA3 (phosphorylated); mediates
CC EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with
CC FLT4 (tyrosine-phosphorylated). Isoform Crk-II (via SH2 domain)
CC interacts with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine
CC phosphorylated). Part of a collagen stimulated complex involved in cell
CC migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts
CC (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1.
CC Interacts with CBLC (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:P46108}.
CC -!- INTERACTION:
CC Q63768; P18031: PTPN1; Xeno; NbExp=2; IntAct=EBI-8423843, EBI-968788;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Note=Translocated to
CC the plasma membrane upon cell adhesion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Crk-II;
CC IsoId=Q63768-1; Sequence=Displayed;
CC Name=Crk-I;
CC IsoId=Q63768-2; Sequence=VSP_004175;
CC -!- TISSUE SPECIFICITY: CRK-II is expressed in all tissues and cells
CC whereas CRK-I is expressed at lower level and in limited cell-types.
CC -!- DOMAIN: The C-terminal SH3 domain function as a negative modulator for
CC transformation and the N-terminal SH3 domain appears to function as a
CC positive regulator for transformation. {ECO:0000250}.
CC -!- DOMAIN: The SH2 domain mediates interaction with tyrosine
CC phosphorylated proteins. Mediates interaction with SHB (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Phosphorylated on Tyr-221 upon cell adhesion. Results in the
CC negative regulation of the association with SH2- and SH3-binding
CC partners, possibly by the formation of an intramolecular interaction of
CC phosphorylated Tyr-221 with the SH2 domain. This leads finally to the
CC down-regulation of the Crk signaling pathway (PubMed:12198159). Isoform
CC Crk-II: Phosphorylated by KIT (By similarity).
CC {ECO:0000250|UniProtKB:P46108, ECO:0000269|PubMed:12198159}.
CC -!- PTM: Proline isomerization at Pro-237 by PPIA acts as a switch between
CC two conformations: an autoinhibitory conformation in the cis form,
CC where the tandem SH3 domains interact intramolecularly, and an
CC activated conformation in the trans form. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the CRK family. {ECO:0000305}.
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DR EMBL; D44481; BAA07924.1; -; mRNA.
DR RefSeq; NP_062175.1; NM_019302.1. [Q63768-1]
DR AlphaFoldDB; Q63768; -.
DR BMRB; Q63768; -.
DR SMR; Q63768; -.
DR BioGRID; 248468; 4.
DR CORUM; Q63768; -.
DR IntAct; Q63768; 12.
DR MINT; Q63768; -.
DR STRING; 10116.ENSRNOP00000006407; -.
DR iPTMnet; Q63768; -.
DR PhosphoSitePlus; Q63768; -.
DR jPOST; Q63768; -.
DR PaxDb; Q63768; -.
DR PRIDE; Q63768; -.
DR Ensembl; ENSRNOT00000006407; ENSRNOP00000006407; ENSRNOG00000025792. [Q63768-1]
DR GeneID; 54245; -.
DR KEGG; rno:54245; -.
DR CTD; 1398; -.
DR RGD; 2405; Crk.
DR eggNOG; KOG4792; Eukaryota.
DR GeneTree; ENSGT00820000127055; -.
DR HOGENOM; CLU_060542_0_1_1; -.
DR InParanoid; Q63768; -.
DR OMA; WWNAEDG; -.
DR OrthoDB; 1414461at2759; -.
DR PhylomeDB; Q63768; -.
DR TreeFam; TF321436; -.
DR Reactome; R-RNO-170984; ARMS-mediated activation.
DR Reactome; R-RNO-186763; Downstream signal transduction.
DR Reactome; R-RNO-2029482; Regulation of actin dynamics for phagocytic cup formation.
DR Reactome; R-RNO-372708; p130Cas linkage to MAPK signaling for integrins.
DR Reactome; R-RNO-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-RNO-8849471; PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases.
DR Reactome; R-RNO-8875555; MET activates RAP1 and RAC1.
DR Reactome; R-RNO-8875656; MET receptor recycling.
DR Reactome; R-RNO-912631; Regulation of signaling by CBL.
DR PRO; PR:Q63768; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Bgee; ENSRNOG00000025792; Expressed in duodenum and 19 other tissues.
DR Genevisible; Q63768; RN.
DR GO; GO:0015629; C:actin cytoskeleton; ISO:RGD.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016020; C:membrane; IDA:RGD.
DR GO; GO:0045121; C:membrane raft; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0008092; F:cytoskeletal protein binding; IPI:RGD.
DR GO; GO:0019899; F:enzyme binding; IPI:RGD.
DR GO; GO:0046875; F:ephrin receptor binding; ISO:RGD.
DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:RGD.
DR GO; GO:0019900; F:kinase binding; ISO:RGD.
DR GO; GO:0001784; F:phosphotyrosine residue binding; ISO:RGD.
DR GO; GO:0019904; F:protein domain specific binding; IPI:RGD.
DR GO; GO:0045309; F:protein phosphorylated amino acid binding; ISO:RGD.
DR GO; GO:0043621; F:protein self-association; ISO:RGD.
DR GO; GO:1990782; F:protein tyrosine kinase binding; IPI:RGD.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; IMP:RGD.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0097110; F:scaffold protein binding; IPI:RGD.
DR GO; GO:0042169; F:SH2 domain binding; ISO:RGD.
DR GO; GO:0017124; F:SH3 domain binding; ISO:RGD.
DR GO; GO:0035591; F:signaling adaptor activity; ISO:RGD.
DR GO; GO:0030159; F:signaling receptor complex adaptor activity; ISO:RGD.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0090630; P:activation of GTPase activity; ISO:RGD.
DR GO; GO:0060326; P:cell chemotaxis; ISO:RGD.
DR GO; GO:0016477; P:cell migration; IBA:GO_Central.
DR GO; GO:0008283; P:cell population proliferation; ISO:RGD.
DR GO; GO:1990859; P:cellular response to endothelin; IPI:RGD.
DR GO; GO:1990314; P:cellular response to insulin-like growth factor stimulus; IPI:RGD.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IDA:RGD.
DR GO; GO:0071732; P:cellular response to nitric oxide; IPI:RGD.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IPI:RGD.
DR GO; GO:0098749; P:cerebellar neuron development; ISO:RGD.
DR GO; GO:0021987; P:cerebral cortex development; ISO:RGD.
DR GO; GO:0016358; P:dendrite development; ISO:RGD.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0030010; P:establishment of cell polarity; ISO:RGD.
DR GO; GO:0035685; P:helper T cell diapedesis; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; ISO:RGD.
DR GO; GO:0006629; P:lipid metabolic process; ISO:RGD.
DR GO; GO:2000146; P:negative regulation of cell motility; ISO:RGD.
DR GO; GO:0045953; P:negative regulation of natural killer cell mediated cytotoxicity; IMP:RGD.
DR GO; GO:0061045; P:negative regulation of wound healing; ISO:RGD.
DR GO; GO:0001764; P:neuron migration; ISO:RGD.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:RGD.
DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IMP:RGD.
DR GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; ISS:UniProtKB.
DR GO; GO:0072657; P:protein localization to membrane; IMP:RGD.
DR GO; GO:0038026; P:reelin-mediated signaling pathway; ISO:RGD.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0033628; P:regulation of cell adhesion mediated by integrin; ISO:RGD.
DR GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR GO; GO:0050773; P:regulation of dendrite development; ISO:RGD.
DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:1902531; P:regulation of intracellular signal transduction; ISO:RGD.
DR GO; GO:0002685; P:regulation of leukocyte migration; ISO:RGD.
DR GO; GO:0043393; P:regulation of protein binding; ISO:RGD.
DR GO; GO:0035020; P:regulation of Rac protein signal transduction; IMP:RGD.
DR GO; GO:0009966; P:regulation of signal transduction; ISO:RGD.
DR GO; GO:2000404; P:regulation of T cell migration; ISO:RGD.
DR GO; GO:0061847; P:response to cholecystokinin; IDA:RGD.
DR GO; GO:0035728; P:response to hepatocyte growth factor; IPI:RGD.
DR GO; GO:0042542; P:response to hydrogen peroxide; IPI:RGD.
DR GO; GO:1901652; P:response to peptide; IPI:RGD.
DR GO; GO:0001878; P:response to yeast; IEP:RGD.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd11759; SH3_CRK_C; 1.
DR CDD; cd11758; SH3_CRK_N; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR035458; CRK_SH3_C.
DR InterPro; IPR035457; CRK_SH3_N.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF00018; SH3_1; 1.
DR Pfam; PF07653; SH3_2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00452; SH3DOMAIN.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00326; SH3; 2.
DR SUPFAM; SSF50044; SSF50044; 2.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
DR PROSITE; PS50002; SH3; 2.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell membrane; Cytoplasm; Membrane;
KW Phosphoprotein; Proto-oncogene; Reference proteome; Repeat; SH2 domain;
KW SH3 domain.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT CHAIN 2..304
FT /note="Adapter molecule crk"
FT /id="PRO_0000079353"
FT DOMAIN 13..118
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 132..192
FT /note="SH3 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 235..296
FT /note="SH3 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT REGION 61..85
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 201..229
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 66..82
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 237
FT /note="Proline switch"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 40
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 41
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 74
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 108
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 125
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT MOD_RES 221
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000269|PubMed:12198159"
FT MOD_RES 239
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P46108"
FT VAR_SEQ 205..304
FT /note="Missing (in isoform Crk-I)"
FT /evidence="ECO:0000305"
FT /id="VSP_004175"
FT VARIANT 244
FT /note="Q -> R (in NRK-23 inactive mutant)"
FT VARIANT 253
FT /note="K -> E (in NRK-23 inactive mutant)"
FT MUTAGEN 221
FT /note="Y->F: No activation of Rac signaling."
FT /evidence="ECO:0000269|PubMed:12198159"
SQ SEQUENCE 304 AA; 33845 MW; 4CFBFB65BE72E265 CRC64;
MAGNFDSEER SSWYWGRLSR QEAVALLQGQ RHGVFLVRDS STSPGDYVLS VSENSRVSHY
IINSSGPRPP VPPSPAQPPP GVSPSRLRIG DQEFDSLPAL LEFYKIHYLD TTTLIEPVSR
SRQGSGVILR QEEAEYVRAL FDFNGNDEED LPFKKGDILR IRDKPEEQWW NAEDSEGKRG
MIPVPYVEKY RPASASVSAL IGGNQEGSHP QPLGGPEPGP YAQPSVNTPL PNLQNGPIYA
RVIQKRVPNA YDKTALALEV GELVKVTKIN VSGQWEGECN GKRGHFPFTH VRLLDQQNPE
EDFS
