P05480 (SRC_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 161. History...
Names and origin
|Protein names||Recommended name:|
Neuronal proto-oncogene tyrosine-protein kinase Src
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||541 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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). 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). 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. Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors. Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation. 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 ADRBK1, 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. 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. 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. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase. Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-132'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Ref.7 Ref.9 Ref.13 Ref.15
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Phosphorylation by CSK at Tyr-535 inhibits kinase activity. Inhibitory phosphorylation at Tyr-535 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-424 increases kinase activity. Ref.8
Interacts with CDCP1, PELP1, TGFB1I1 and TOM1L2. Interacts with DDEF1/ASAP1 via its SH3 domain. Interacts with CCPG1. Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin. Interacts with RALGPS1 via its SH3 domain. Interacts with CAV2 (tyrosine phosphorylated form). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus. Interacts with FCAMR and PXN. Interacts with ARRB2. Interacts with ARRB1. Interacts with SRCIN1. Interacts with SRCIN1. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1, ESR1 (dimethylated on arginine) and FAK. Interacts (via SH2 and SH3 domain) with TNK2. Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain). Interacts with TRAF3 (via RING-type zinc finger domain). Interacts with DDX58, MAVS and TBK1. Interacts (via SH2 domain) with GNB2L1/RACK1; the interaction is enhanced by tyrosine phosphorylation of GNB2L1 and inhibits SRC activity. Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration. Interacts with ERBB2 and STAT1. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with CSF1R. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1. Interacts with DDR2. Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites. Interacts with DDR1 and DAB2. Interacts with TRAP1. Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-424'. Ref.5 Ref.6 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16 Ref.17 Ref.20 Ref.21
Cell membrane. Mitochondrion inner membrane. Nucleus. Cytoplasm › cytoskeleton. Note: Localizes to focal adhesion sites after integrin engagement. Localization to focal adhesion sites requires myristoylation and the SH3 domain. Ref.13
Myristoylated at Gly-2, and this is essential for targeting to membranes By similarity.
Dephosphorylated at Tyr-535 by PTPRJ By similarity. Phosphorylated on Tyr-535 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-424. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-535, the SH3 domain engaged with the SH2-kinase linker, and Tyr-424 dephosphorylated. Dephosphorylation of Tyr-535 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-535, Tyr-424 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-535 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-74 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 By similarity.
S-nitrosylation is important for activation of its kinase activity By similarity.
Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-424 and may lead to lysosomal degradation By similarity.
Contains 1 protein kinase domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.
|Bcar1||Q63767||2||EBI-298680,EBI-1176801||From a different organism.|
|Dlg4||P31016||9||EBI-298680,EBI-375655||From a different organism.|
|ena||Q8T4F7||2||EBI-298680,EBI-466810||From a different organism.|
|Grin2a||Q00959||5||EBI-298680,EBI-630970||From a different organism.|
|ITGB3||P05106||5||EBI-298680,EBI-702847||From a different organism.|
|PTK2||Q05397||5||EBI-298680,EBI-702142||From a different organism.|
|PXN||P49023||2||EBI-298680,EBI-702209||From a different organism.|
|ROR1||Q01973||3||EBI-298680,EBI-6082337||From a different organism.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 541||540||Neuronal proto-oncogene tyrosine-protein kinase Src||PRO_0000088142|
|Domain||83 – 150||68||SH3|
|Domain||156 – 253||98||SH2|
|Domain||275 – 528||254||Protein kinase|
|Nucleotide binding||281 – 289||9||ATP By similarity|
|Active site||394||1||Proton acceptor By similarity|
|Binding site||303||1||ATP By similarity|
Amino acid modifications
|Modified residue||17||1||Phosphoserine By similarity|
|Modified residue||34||1||Phosphoserine By similarity|
|Modified residue||68||1||Phosphoserine By similarity|
|Modified residue||73||1||Phosphothreonine By similarity|
|Modified residue||74||1||Phosphoserine; by CDK5 By similarity|
|Modified residue||192||1||Phosphotyrosine Ref.18|
|Modified residue||424||1||Phosphotyrosine; by autocatalysis; alternate By similarity|
|Modified residue||424||1||Phosphotyrosine; by FAK2; alternate By similarity|
|Modified residue||444||1||Phosphotyrosine By similarity|
|Modified residue||516||1||Phosphothreonine By similarity|
|Modified residue||527||1||Phosphotyrosine By similarity|
|Modified residue||535||1||Phosphotyrosine; by CSK By similarity|
|Lipidation||2||1||N-myristoyl glycine By similarity|
|Sequence conflict||80||1||P → A in AAA40135. Ref.1|
|||"Neuronal pp60c-src contains a six-amino acid insertion relative to its non-neuronal counterpart."|
Martinez R., Mathey-Prevot B., Bernards A., Baltimore D.
Science 237:411-415(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Characterization of quantitative trait loci influencing growth and adiposity using congenic mouse strains."|
Farber C.R., Corva P.M., Medrano J.F.
Submitted (JAN-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||"Lineage-specific biology revealed by a finished genome assembly of the mouse."|
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.|
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"Activation of Src family kinases by colony stimulating factor-1, and their association with its receptor."|
Courtneidge S.A., Dhand R., Pilat D., Twamley G.M., Waterfield M.D., Roussel M.F.
EMBO J. 12:943-950(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CSF1R.
|||"Direct and specific interaction of c-Src with Neu is involved in signaling by the epidermal growth factor receptor."|
Muthuswamy S.K., Muller W.J.
Oncogene 11:271-279(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ERBB2.
|||"Activation of Src-family protein tyrosine kinases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipocytes by interleukin-11."|
Fuhrer D.K., Yang Y.C.
Exp. Hematol. 24:195-203(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN IL11-SIGNALING.
|||"Bombesin, bradykinin, vasopressin, and phorbol esters rapidly and transiently activate Src family tyrosine kinases in Swiss 3T3 cells. Dissociation from tyrosine phosphorylation of p125 focal adhesion kinase."|
Rodriguez-Fernandez J.L., Rozengurt E.
J. Biol. Chem. 271:27895-27901(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION.
|||"c-Src activates both STAT1 and STAT3 in PDGF-stimulated NIH3T3 cells."|
Cirri P., Chiarugi P., Marra F., Raugei G., Camici G., Manao G., Ramponi G.
Biochem. Biophys. Res. Commun. 239:493-497(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH STAT1.
|||"ASAP1, a phospholipid-dependent arf GTPase-activating protein that associates with and is phosphorylated by Src."|
Brown M.T., Andrade J., Radhakrishna H., Donaldson J.G., Cooper J.A., Randazzo P.A.
Mol. Cell. Biol. 18:7038-7051(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DDEF1/ASAP1.
|||"N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling."|
Cavallaro U., Niedermeyer J., Fuxa M., Christofori G.
Nat. Cell Biol. 3:650-657(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH NCAM1; CDH2; PLCG1; FRS2; FGFR4; SHC1; GAP43 AND CTTN.
|||"The role of c-Src in platelet-derived growth factor alpha receptor internalization."|
Avrov K., Kazlauskas A.
Exp. Cell Res. 291:426-434(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PDGFRA.
|||"Regulation of cytochrome c oxidase activity by c-Src in osteoclasts."|
Miyazaki T., Neff L., Tanaka S., Horne W.C., Baron R.
J. Cell Biol. 160:709-718(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
|||"EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis."|
Vindis C., Cerretti D.P., Daniel T.O., Huynh-Do U.
J. Cell Biol. 162:661-671(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EPHB1.
|||"Src kinase activity is essential for osteoclast function."|
Miyazaki T., Sanjay A., Neff L., Tanaka S., Horne W.C., Baron R.
J. Biol. Chem. 279:17660-17666(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH PTK2B/PYK2.
|||"Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2."|
Heiss E., Masson K., Sundberg C., Pedersen M., Sun J., Bengtsson S., Ronnstrand L.
Blood 108:1542-1550(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FLT3.
|||"Ccpg1, a novel scaffold protein that regulates the activity of the Rho guanine nucleotide exchange factor Dbs."|
Kostenko E.V., Olabisi O.O., Sahay S., Rodriguez P.L., Whitehead I.P.
Mol. Cell. Biol. 26:8964-8975(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CCPG1.
|||"Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain."|
Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.
J. Proteome Res. 7:311-318(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-192, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"The phagosomal proteome in interferon-gamma-activated macrophages."|
Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance."|
Luan B., Zhao J., Wu H., Duan B., Shu G., Wang X., Li D., Jia W., Kang J., Pei G.
Nature 457:1146-1149(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
|||"Collagen stimulates discoidin domain receptor 1-mediated migration of smooth muscle cells through Src."|
Lu K.K., Trcka D., Bendeck M.P.
Cardiovasc. Pathol. 20:71-76(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DDR1.
|||"Regulation, substrates and functions of src."|
Brown M.T., Cooper J.A.
Biochim. Biophys. Acta 1287:121-149(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Cellular functions regulated by Src family kinases."|
Thomas S.M., Brugge J.S.
Annu. Rev. Cell Dev. Biol. 13:513-609(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Novel regulation and function of Src tyrosine kinase."|
Ma Y.C., Huang X.Y.
Cell. Mol. Life Sci. 59:456-462(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|+||Additional computationally mapped references.|
|M17031 mRNA. Translation: AAA40135.1.|
AY902331 Genomic DNA. Translation: AAX90616.1.
AL672259 Genomic DNA. Translation: CAM16141.1.
CH466551 Genomic DNA. Translation: EDL06234.1.
|RefSeq||NP_001020566.1. NM_001025395.2. |
3D structure databases
|SMR||P05480. Positions 56-541. |
Protein-protein interaction databases
|BioGrid||203491. 37 interactions.|
|IntAct||P05480. 27 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000092576; ENSMUSP00000090237; ENSMUSG00000027646. |
ENSMUST00000109529; ENSMUSP00000105155; ENSMUSG00000027646.
|UCSC||uc008npa.1. mouse. |
|MGI||MGI:98397. Src. |
Enzyme and pathway databases
|BRENDA||18.104.22.168. 3474. |
|Reactome||REACT_188257. Signal Transduction. |
REACT_188576. Developmental Biology.
REACT_23985. Src is activated.
Gene expression databases
Family and domain databases
|Gene3D||3.30.505.10. 1 hit. |
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
|PRINTS||PR00401. SH2DOMAIN. |
|SMART||SM00252. SH2. 1 hit. |
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF50044. SSF50044. 1 hit. |
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
|Accession||Primary (citable) accession number: P05480|
Secondary accession number(s): Q2M4I4
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|