SRC

This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase

Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625).
In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity).
Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730).
Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953).
Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507).
Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:8755529, PubMed:14585963).
Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910).
Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108).
Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750).
Enhances DDX58/RIG-I-elicited antiviral signaling (PubMed:19419966).
Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963).
Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723).
Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694).
Phosphorylates synaptic vesicle protein synaptophysin (SYP) (By similarity).
Involved in anchorage-independent cell growth (PubMed:19307596).
Required for podosome formation (By similarity).
Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159).
Isoform 1
Non-receptor protein tyrosine kinase which phosphorylates synaptophysin with high affinity.
Isoform 2
Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity).
The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity).
Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity).
Plays a role in L1CAM-mediated neurite elongation, possibly by acting downstream of L1CAM to drive cytoskeletal rearrangements involved in neurite outgrowth (By similarity).
Isoform 3
Non-receptor protein tyrosine kinase which shows higher basal kinase activity than isoform 1, possibly due to weakened intramolecular interactions which enhance autophosphorylation of Tyr-419 and subsequent activation (By similarity).
The SH3 domain shows reduced affinity with the linker sequence between the SH2 and kinase domains which may account for the increased basal activity (By similarity).
Displays altered substrate specificity compared to isoform 1, showing weak affinity for synaptophysin and for peptide substrates containing class I or class II SH3 domain-binding motifs (By similarity).
Plays a role in neurite elongation (By similarity).

Activation of protein kinase B activityIEA:Ensembl
Adherens junction organizationIEA:Ensembl
Angiotensin-activated signaling pathway involved in heart processISS:BHF-UCL
Bone resorptionISS:UniProtKB
Branching involved in mammary gland duct morphogenesisIEA:Ensembl
Cell adhesionManual Assertion Based On ExperimentIBA:GO_Central
Cell cycleIEA:UniProtKB-KW
Cell differentiationManual Assertion Based On ExperimentIBA:GO_Central
Cell population proliferationIEA:Ensembl
Cell-cell adhesionIEA:Ensembl
Cellular response to fatty acidIEA:Ensembl
Cellular response to fluid shear stressIEA:Ensembl
Cellular response to hydrogen peroxideIEA:Ensembl
Cellular response to hypoxiaIEA:Ensembl
Cellular response to insulin stimulusIEA:Ensembl
Cellular response to lipopolysaccharideIEA:Ensembl
Cellular response to peptide hormone stimulusISS:BHF-UCL
Cellular response to platelet-derived growth factor stimulusIEA:Ensembl
Cellular response to progesterone stimulusISS:BHF-UCL
Entry of bacterium into host cellTAS:Reactome
Ephrin receptor signaling pathwayTAS:Reactome
Epidermal growth factor receptor signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
ERBB2 signaling pathwayTAS:Reactome
Fc-gamma receptor signaling pathway involved in phagocytosisTAS:Reactome
Focal adhesion assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Forebrain developmentIEA:Ensembl
Innate immune responseManual Assertion Based On ExperimentIBA:GO_Central
Integrin-mediated signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Interleukin-6-mediated signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Intestinal epithelial cell developmentManual Assertion Based On ExperimentIDA:UniProtKB
Intracellular signal transductionManual Assertion Based On ExperimentIDA:ARUK-UCL
Leukocyte migrationTAS:Reactome
MacroautophagyTAS:Reactome
Negative regulation of anoikisManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of apoptotic processManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of extrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of focal adhesion assemblyISS:BHF-UCL
Negative regulation of inflammatory response to antigenic stimulusTAS:Reactome
Negative regulation of intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of mitochondrial depolarizationManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of protein-containing complex assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of telomerase activityManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of telomere maintenance via telomeraseManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of transcription, DNA-templatedIEA:Ensembl
Neurotrophin TRK receptor signaling pathwayIEA:Ensembl
OdontogenesisIEA:Ensembl
OogenesisIEA:Ensembl
Osteoclast developmentManual Assertion Based On ExperimentIBA:GO_Central
Peptidyl-serine phosphorylationIEA:Ensembl
Peptidyl-tyrosine autophosphorylationIEA:Ensembl
Peptidyl-tyrosine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Platelet activationTAS:Reactome
Positive regulation of apoptotic processIEA:Ensembl
Positive regulation of canonical Wnt signaling pathwayIEA:Ensembl
Positive regulation of cyclin-dependent protein serine/threonine kinase activityIEA:Ensembl
Positive regulation of cytokine productionIEA:Ensembl
Positive regulation of dephosphorylationManual Assertion Based On ExperimentIDA:ARUK-UCL
Positive regulation of DNA biosynthetic processIEA:Ensembl
Positive regulation of epithelial cell migrationManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of ERK1 and ERK2 cascadeIEA:Ensembl
Positive regulation of glucose metabolic processIEA:Ensembl
Positive regulation of insulin receptor signaling pathwayIEA:Ensembl
Positive regulation of integrin activationManual Assertion Based On ExperimentTAS:BHF-UCL
Positive regulation of lamellipodium morphogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of MAP kinase activityIEA:Ensembl
Positive regulation of non-membrane spanning protein tyrosine kinase activity1 PublicationNAS:ARUK-UCL
Positive regulation of Notch signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of ovarian follicle developmentIEA:Ensembl
Positive regulation of peptidyl-tyrosine phosphorylationManual Assertion Based On ExperimentIMP:ARUK-UCL
Positive regulation of phosphatidylinositol 3-kinase activityIEA:Ensembl
Positive regulation of phosphatidylinositol 3-kinase signalingTAS:Reactome
Positive regulation of platelet-derived growth factor receptor-beta signaling pathwayIEA:Ensembl
Positive regulation of podosome assemblyIEA:Ensembl
Positive regulation of protein autophosphorylationIEA:Ensembl
Positive regulation of protein kinase B signalingManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of protein localization to nucleusIEA:Ensembl
Positive regulation of protein processingIEA:Ensembl
Positive regulation of protein serine/threonine kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of protein transportIEA:Ensembl
Positive regulation of small GTPase mediated signal transductionManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of smooth muscle cell migrationIEA:Ensembl
Positive regulation of transcription, DNA-templatedIEA:Ensembl
Primary ovarian follicle growthIEA:Ensembl
Progesterone receptor signaling pathwayISS:BHF-UCL
Protein autophosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Protein destabilizationIEA:Ensembl
Regulation of bone resorptionManual Assertion Based On ExperimentTAS:BHF-UCL
Regulation of caveolin-mediated endocytosisManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of cell projection assemblyIEA:Ensembl
Regulation of cell-cell adhesionManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of early endosome to late endosome transportManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of epithelial cell migrationManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of intracellular estrogen receptor signaling pathwayIEA:Ensembl
Regulation of postsynaptic neurotransmitter receptor activityIEA:Ensembl
Regulation of protein bindingIEA:Ensembl
Regulation of vascular permeabilityManual Assertion Based On ExperimentTAS:BHF-UCL
Response to acidic pHIEA:Ensembl
Response to electrical stimulusIEA:Ensembl
Response to interleukin-1Manual Assertion Based On ExperimentIMP:BHF-UCL
Response to mechanical stimulusIEA:Ensembl
Response to mineralocorticoidIEA:Ensembl
Response to nutrient levelsIEA:Ensembl
Response to virusIEA:Ensembl
Response to xenobiotic stimulusIEA:Ensembl
Signal complex assemblyManual Assertion Based On ExperimentTAS:ProtInc
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Stimulatory C-type lectin receptor signaling pathwayTAS:Reactome
Stress fiber assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Substrate adhesion-dependent cell spreadingIEA:Ensembl
T cell costimulationTAS:Reactome
TranscytosisIEA:Ensembl
Transforming growth factor beta receptor signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Transmembrane receptor protein tyrosine kinase signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central
Uterus developmentIEA:Ensembl
Vascular endothelial growth factor receptor signaling pathwayTAS:Reactome

Cell membrane
Mitochondrion inner membrane
Nucleus
Cytoplasm, cytoskeleton
Cytoplasm, perinuclear region
Cell junction, focal adhesion
Localizes to focal adhesion sites following integrin engagement (PubMed:22801373).
Localization to focal adhesion sites requires myristoylation and the SH3 domain (PubMed:7525268).
Colocalizes with PDLIM4 at the perinuclear region, but not at focal adhesions (PubMed:19307596).

Thrombocytopenia 6 (THC6):
A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC6 is an autosomal dominant form. Affected individuals may also have bone abnormalities and an increased risk for myelofibrosis.

Myristoylated at Gly-2, and this is essential for targeting to membranes.
Dephosphorylated at Tyr-530 by PTPRJ (By similarity).
Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (PubMed:25731159).
Isoform 1
Displays reduced levels of autophosphorylation at Tyr-419 compared to isoforms 2 and 3.
Isoform 2
Displays enhanced levels of autophosphorylation at Tyr-419 compared to isoform 1.
Isoform 3
Displays enhanced levels of autophosphorylation at Tyr-419 compared to isoform 1 (By similarity).
Shows reduced phosphorylation at Tyr-527 compared to isoforms 1 and 2 (By similarity).
S-nitrosylation is important for activation of its kinase activity.
Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation.