UniProt functional annotation for P46108



	UniProt functional annotation for P46108

UniProt code: P46108.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Involved in cell branching and adhesion mediated by BCAR1- CRK-RAPGEF1 signaling and activation of RAP1. {ECO:0000269|PubMed:12432078}.

Function: [Isoform Crk-II]: Regulates cell adhesion, spreading and migration (PubMed:31311869). Mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4 (PubMed:19004829). May regulate the EFNA5-EPHA3 signaling (By similarity). {ECO:0000250|UniProtKB:Q64010, ECO:0000269|PubMed:11870224, ECO:0000269|PubMed:1630456, ECO:0000269|PubMed:17515907, ECO:0000269|PubMed:19004829, ECO:0000269|PubMed:31311869}.

Subunit: Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C- terminus), and BCAR1/CAS (PubMed:12432078). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (PubMed:19381274). Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with CBLC. {ECO:0000269|PubMed:10362357, ECO:0000269|PubMed:10964504, ECO:0000269|PubMed:12384576, ECO:0000269|PubMed:12432078, ECO:0000269|PubMed:12628187, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18024423, ECO:0000269|PubMed:19381274, ECO:0000269|PubMed:19807924, ECO:0000269|PubMed:20534451, ECO:0000269|PubMed:8657152, ECO:0000269|PubMed:8662907, ECO:0000269|PubMed:9614078}.

Subunit: [Isoform Crk-II]: Interacts (via SH2 domain) with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated) (PubMed:10733900). Interacts with EPHA3 (phosphorylated); upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent and mediates EFNA5-EPHA3 signaling through RHOA GTPase activation (PubMed:11870224). Interacts with KIT (PubMed:12878163). Interacts with PEAK3; the interaction requires PEAK3 homodimerization (PubMed:31311869). {ECO:0000269|PubMed:10733900, ECO:0000269|PubMed:11870224, ECO:0000269|PubMed:12878163, ECO:0000269|PubMed:31311869}.

Subcellular location: Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}. Note=Translocated to the plasma membrane upon cell adhesion. {ECO:0000250}.

Domain: The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation. {ECO:0000250}.

Domain: The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.

Ptm: Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway (PubMed:17515907). Isoform Crk-II: Phosphorylated by KIT (By similarity). {ECO:0000250|UniProtKB:Q64010, ECO:0000269|PubMed:17515907}.

Ptm: Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form. {ECO:0000250}.

Similarity: Belongs to the CRK family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Involved in cell branching and adhesion mediated by BCAR1- CRK-RAPGEF1 signaling and activation of RAP1. {ECO:0000269\|PubMed:12432078}.



Function:		[Isoform Crk-II]: Regulates cell adhesion, spreading and migration (PubMed:31311869). Mediates attachment-induced MAPK8 activation, membrane ruffling and cell motility in a Rac-dependent manner. Involved in phagocytosis of apoptotic cells and cell motility via its interaction with DOCK1 and DOCK4 (PubMed:19004829). May regulate the EFNA5-EPHA3 signaling (By similarity). {ECO:0000250\|UniProtKB:Q64010, ECO:0000269\|PubMed:11870224, ECO:0000269\|PubMed:1630456, ECO:0000269\|PubMed:17515907, ECO:0000269\|PubMed:19004829, ECO:0000269\|PubMed:31311869}.


Subunit:		Component of a complex comprised of SH2D3C, BCAR1/CAS, and CRK (PubMed:12432078). Within the complex, interacts with SH2D3C (via C- terminus), and BCAR1/CAS (PubMed:12432078). Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases (PubMed:19381274). Interacts with ABL1, C3G, DOCK3, DOCK5, MAP4K1, MAPK8 and SOS via its first SH3 domain. Interacts (via SH2 domain) with BCAR1, CBL, CBLB, PXN, IRS4 and GAB1 upon stimulus-induced tyrosine phosphorylation. Interacts (via SH2 domain) with several tyrosine-phosphorylated growth factor receptors such as EGFR and INSR. Interacts with FLT1 (tyrosine-phosphorylated). Interacts with DOCK1 and DOCK4. Interacts with SHB. Interacts with PEAK1. Interacts with FASLG. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and p130cas/BCAR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with CBLC. {ECO:0000269\|PubMed:10362357, ECO:0000269\|PubMed:10964504, ECO:0000269\|PubMed:12384576, ECO:0000269\|PubMed:12432078, ECO:0000269\|PubMed:12628187, ECO:0000269\|PubMed:12878163, ECO:0000269\|PubMed:16076871, ECO:0000269\|PubMed:17038317, ECO:0000269\|PubMed:18024423, ECO:0000269\|PubMed:19381274, ECO:0000269\|PubMed:19807924, ECO:0000269\|PubMed:20534451, ECO:0000269\|PubMed:8657152, ECO:0000269\|PubMed:8662907, ECO:0000269\|PubMed:9614078}.
Subunit:		[Isoform Crk-II]: Interacts (via SH2 domain) with PDGFRA (tyrosine phosphorylated) and PDGFRB (tyrosine phosphorylated) (PubMed:10733900). Interacts with EPHA3 (phosphorylated); upon activation of EPHA3 by the ligand EFNA5 and EPHA3 tyrosine kinase activity-dependent and mediates EFNA5-EPHA3 signaling through RHOA GTPase activation (PubMed:11870224). Interacts with KIT (PubMed:12878163). Interacts with PEAK3; the interaction requires PEAK3 homodimerization (PubMed:31311869). {ECO:0000269\|PubMed:10733900, ECO:0000269\|PubMed:11870224, ECO:0000269\|PubMed:12878163, ECO:0000269\|PubMed:31311869}.
Subcellular location:		Cytoplasm {ECO:0000250}. Cell membrane {ECO:0000250}. Note=Translocated to the plasma membrane upon cell adhesion. {ECO:0000250}.
Domain:		The C-terminal SH3 domain function as a negative modulator for transformation and the N-terminal SH3 domain appears to function as a positive regulator for transformation. {ECO:0000250}.
Domain:		The SH2 domain mediates interaction with tyrosine phosphorylated proteins. Mediates interaction with SHB.
Ptm:		Phosphorylated on Tyr-221 upon cell adhesion. Results in the negative regulation of the association with SH2- and SH3-binding partners, possibly by the formation of an intramolecular interaction of phosphorylated Tyr-221 with the SH2 domain. This leads finally to the down-regulation of the Crk signaling pathway (PubMed:17515907). Isoform Crk-II: Phosphorylated by KIT (By similarity). {ECO:0000250\|UniProtKB:Q64010, ECO:0000269\|PubMed:17515907}.
Ptm:		Proline isomerization at Pro-237 by PPIA acts as a switch between two conformations: an autoinhibitory conformation in the cis form, where the tandem SH3 domains interact intramolecularly, and an activated conformation in the trans form. {ECO:0000250}.
Similarity:		Belongs to the CRK family. {ECO:0000305}.