UniProt functional annotation for Q07912



	UniProt functional annotation for Q07912

UniProt code: Q07912.

Organism: Homo sapiens (Human).

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

Function: Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370). {ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:11278436, ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:18262180, ECO:0000269|PubMed:18435854, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20110370, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20383201}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:18993068, ECO:0000269|PubMed:20333297};

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:18993068};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:18993068};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:10652228, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:20333297};

Activity regulation: Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3- d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib. {ECO:0000269|PubMed:20383201, ECO:0000269|PubMed:20623637}.

Subunit: Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By similarity). Homodimer. Interacts with AR, CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). Interacts with MERTK (activated); stimulates autophosphorylation. May interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2. {ECO:0000250, ECO:0000269|PubMed:10587647, ECO:0000269|PubMed:16137687, ECO:0000269|PubMed:16257963, ECO:0000269|PubMed:16288044, ECO:0000269|PubMed:17038317, ECO:0000269|PubMed:17494760, ECO:0000269|PubMed:18477472, ECO:0000269|PubMed:18993068, ECO:0000269|PubMed:19144635, ECO:0000269|PubMed:19815557, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20979614, ECO:0000269|PubMed:21309750, ECO:0000269|PubMed:23686771, ECO:0000269|PubMed:8497321}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20979614}. Nucleus {ECO:0000269|PubMed:14733946, ECO:0000269|PubMed:20333297}. Endosome {ECO:0000250|UniProtKB:O54967}. Cell junction, adherens junction {ECO:0000305}. Cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269|PubMed:16137687}. Cytoplasmic vesicle, clathrin-coated vesicle {ECO:0000269|PubMed:16137687, ECO:0000269|PubMed:18262180}. Membrane, clathrin-coated pit {ECO:0000269|PubMed:21169560}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:20110370}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:O54967}. Note=The Tyr-284 phosphorylated form is found both in the membrane and nucleus (By similarity). Co-localizes with EGFR on endosomes (PubMed:20333297). Nuclear translocation is CDC42-dependent (By similarity). Detected in long filamentous cytosolic structures where it co-localizes with CTPS1 (By similarity). {ECO:0000250|UniProtKB:O54967, ECO:0000269|PubMed:20333297}.

Tissue specificity: The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269|PubMed:16247015, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637}.

Domain: The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR. {ECO:0000250}.

Domain: The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation. {ECO:0000269|PubMed:20979614}.

Domain: The UBA domain binds both poly- and mono-ubiquitin. {ECO:0000269|PubMed:20979614}.

Ptm: Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits. {ECO:0000269|PubMed:15308621, ECO:0000269|PubMed:16472662, ECO:0000269|PubMed:20333297, ECO:0000269|PubMed:20623637, ECO:0000269|PubMed:20979614, ECO:0000269|PubMed:21169560, ECO:0000269|PubMed:21309750}.

Ptm: Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent (By similarity). {ECO:0000250}.

Miscellaneous: [Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Sequence caution: Sequence=AAH08884.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305}; Sequence=BAD18675.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={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:		Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR. Phosphorylates WASP (PubMed:20110370). {ECO:0000269\|PubMed:10652228, ECO:0000269\|PubMed:11278436, ECO:0000269\|PubMed:16247015, ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:16472662, ECO:0000269\|PubMed:17038317, ECO:0000269\|PubMed:18262180, ECO:0000269\|PubMed:18435854, ECO:0000269\|PubMed:19815557, ECO:0000269\|PubMed:20110370, ECO:0000269\|PubMed:20333297, ECO:0000269\|PubMed:20383201}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:10652228, ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:16472662, ECO:0000269\|PubMed:18993068, ECO:0000269\|PubMed:20333297};
Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:18993068};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:18993068};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:10652228, ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:20333297};
Activity regulation:		Inhibited by AIM-100 (4-amino-5,6-biaryl-furo[2,3- d]pyrimidine), which suppresses activating phosphorylation at Tyr-284. Repressed by dasatinib. {ECO:0000269\|PubMed:20383201, ECO:0000269\|PubMed:20623637}.
Subunit:		Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By similarity). Homodimer. Interacts with AR, CDC42, WWASL and WWOX. Interacts with CSPG4 (activated). Interacts with MERTK (activated); stimulates autophosphorylation. May interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2. {ECO:0000250, ECO:0000269\|PubMed:10587647, ECO:0000269\|PubMed:16137687, ECO:0000269\|PubMed:16257963, ECO:0000269\|PubMed:16288044, ECO:0000269\|PubMed:17038317, ECO:0000269\|PubMed:17494760, ECO:0000269\|PubMed:18477472, ECO:0000269\|PubMed:18993068, ECO:0000269\|PubMed:19144635, ECO:0000269\|PubMed:19815557, ECO:0000269\|PubMed:20333297, ECO:0000269\|PubMed:20979614, ECO:0000269\|PubMed:21309750, ECO:0000269\|PubMed:23686771, ECO:0000269\|PubMed:8497321}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:20333297, ECO:0000269\|PubMed:20979614}. Nucleus {ECO:0000269\|PubMed:14733946, ECO:0000269\|PubMed:20333297}. Endosome {ECO:0000250\|UniProtKB:O54967}. Cell junction, adherens junction {ECO:0000305}. Cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side {ECO:0000269\|PubMed:16137687}. Cytoplasmic vesicle, clathrin-coated vesicle {ECO:0000269\|PubMed:16137687, ECO:0000269\|PubMed:18262180}. Membrane, clathrin-coated pit {ECO:0000269\|PubMed:21169560}. Cytoplasm, perinuclear region {ECO:0000269\|PubMed:20110370}. Cytoplasm, cytosol {ECO:0000250\|UniProtKB:O54967}. Note=The Tyr-284 phosphorylated form is found both in the membrane and nucleus (By similarity). Co-localizes with EGFR on endosomes (PubMed:20333297). Nuclear translocation is CDC42-dependent (By similarity). Detected in long filamentous cytosolic structures where it co-localizes with CTPS1 (By similarity). {ECO:0000250\|UniProtKB:O54967, ECO:0000269\|PubMed:20333297}.
Tissue specificity:		The Tyr-284 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages. It also shows a significant increase in expression in prostate cancers during the progressive stages. {ECO:0000269\|PubMed:16247015, ECO:0000269\|PubMed:20333297, ECO:0000269\|PubMed:20623637}.
Domain:		The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR. {ECO:0000250}.
Domain:		The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation. {ECO:0000269\|PubMed:20979614}.
Domain:		The UBA domain binds both poly- and mono-ubiquitin. {ECO:0000269\|PubMed:20979614}.
Ptm:		Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits. {ECO:0000269\|PubMed:15308621, ECO:0000269\|PubMed:16472662, ECO:0000269\|PubMed:20333297, ECO:0000269\|PubMed:20623637, ECO:0000269\|PubMed:20979614, ECO:0000269\|PubMed:21169560, ECO:0000269\|PubMed:21309750}.
Ptm:		Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent (By similarity). {ECO:0000250}.
Miscellaneous:		[Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. {ECO:0000255\|PROSITE-ProRule:PRU00159}.
Sequence caution:		Sequence=AAH08884.1; Type=Miscellaneous discrepancy; Note=Unlikely isoform. Aberrant splice sites.; Evidence={ECO:0000305}; Sequence=BAD18675.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};