Q9WUD9 (SRC_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 119. History...
Names and origin
|Protein names||Recommended name:|
Proto-oncogene tyrosine-protein kinase Src
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||536 AA.|
|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-738'. Enhances DDX58/RIG-I-elicited antiviral signaling By similarity. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' By similarity. Phosphorylates BCAR1 at 'Tyr-226' By similarity. Ref.6
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 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 By similarity. Phosphorylation at Tyr-419 increases kinase activity. Ref.2
Interacts with DDEF1/ASAP1; via the SH3 domain. Interacts with CCPG1. Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Interacts with ERBB2, STAT1 and PNN. Interacts with CDCP1, PELP1, TGFB1I1 and TOM1L2. Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin. Interacts with RALGPS1; via the SH3 domain. Interacts with HEV ORF3 protein; via the 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 ARRB1 and ARRB2. Interacts with SRCIN1. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine). Interacts with FASLG. Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). 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 with EPHB1; activates the MAPK/ERK cascade to regulate cell migration. Interacts with FCAMR. Interacts with PDGFRA (tyrosine phosphorylated). Interacts with CSF1R. Interacts with DDR1. Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 By similarity. Interacts with AMOTL2; this interaction promotes the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites. Interacts with DDR2 and DAB2. Ref.2 Ref.3 Ref.4 Ref.5 Ref.6
Cell membrane By similarity. Mitochondrion inner membrane By similarity. Nucleus By similarity. Cytoplasm › cytoskeleton By similarity. Note: Localizes to focal adhesion sites after integrin engagement By similarity. Localization to focal adhesion sites requires myristoylation and the SH3 domain By similarity.
Myristoylated at Gly-2, and this is essential for targeting to membranes By similarity.
Dephosphorylated at Tyr-530 by PTPRJ. Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src By similarity. 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 SRX 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 By similarity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Ref.2 Ref.7
S-nitrosylation is important for activation of its kinase activity By similarity.
Ubiquitinated in response to CDK5-mediated phosphorylation.
Contains 1 protein kinase domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 536||536||Proto-oncogene tyrosine-protein kinase Src||PRO_0000088143|
|Domain||84 – 145||62||SH3|
|Domain||151 – 248||98||SH2|
|Domain||270 – 523||254||Protein kinase|
|Nucleotide binding||276 – 284||9||ATP By similarity|
|Active site||389||1||Proton acceptor By similarity|
|Binding site||298||1||ATP By similarity|
Amino acid modifications
|Modified residue||17||1||Phosphoserine By similarity|
|Modified residue||34||1||Phosphoserine By similarity|
|Modified residue||69||1||Phosphoserine By similarity|
|Modified residue||74||1||Phosphothreonine By similarity|
|Modified residue||75||1||Phosphoserine; by CDK5 By similarity|
|Modified residue||187||1||Phosphotyrosine By similarity|
|Modified residue||419||1||Phosphotyrosine; by FAK2 Ref.2|
|Modified residue||420||1||Phosphothreonine; by autocatalysis By similarity|
|Modified residue||439||1||Phosphotyrosine By similarity|
|Modified residue||501||1||S-nitrosocysteine By similarity|
|Modified residue||511||1||Phosphothreonine By similarity|
|Modified residue||522||1||Phosphotyrosine By similarity|
|Modified residue||530||1||Phosphotyrosine; by CSK By similarity|
|Lipidation||2||1||N-myristoyl glycine By similarity|
|||"Rattus norvegicus proto-oncogene encoding tyrosine-protein kinase pp60-c-src."|
Stockand J.D., Al-Khalili O., Spier B.J., Eaton D.C.
Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation."|
Dikic I., Tokiwa G., Lev S., Courtneidge S.A., Schlessinger J.
Nature 383:547-550(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PTK2B/PYK2, ENZYME REGULATION, PHOSPHORYLATION AT TYR-419.
|||"The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex."|
DeFea K.A., Vaughn Z.D., O'Bryan E.M., Nishijima D., Dery O., Bunnett N.W.
Proc. Natl. Acad. Sci. U.S.A. 97:11086-11091(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB1.
|||"Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen."|
Ikeda K., Wang L.H., Torres R., Zhao H., Olaso E., Eng F.J., Labrador P., Klein R., Lovett D., Yancopoulos G.D., Friedman S.L., Lin H.C.
J. Biol. Chem. 277:19206-19212(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DDR2.
|||"Characterization of a novel negative regulator (DOC-2/DAB2) of c-Src in normal prostatic epithelium and cancer."|
Zhou J., Scholes J., Hsieh J.T.
J. Biol. Chem. 278:6936-6941(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DAB2.
|||"Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation."|
Yang K., Kim J.H., Kim H.J., Park I.S., Kim I.Y., Yang B.S.
J. Biol. Chem. 280:39058-39066(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DDR2.
|||"The rat tyrosine phosphatase eta increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue."|
Pera I.L., Iuliano R., Florio T., Susini C., Trapasso F., Santoro M., Chiariotti L., Schettini G., Viglietto G., Fusco A.
Oncogene 24:3187-3195(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-530, DEPHOSPHORYLATION BY PTPRJ AT TYR-530.
|+||Additional computationally mapped references.|
|AF130457 mRNA. Translation: AAD24180.1.|
3D structure databases
|SMR||Q9WUD9. Positions 86-536. |
Protein-protein interaction databases
Protocols and materials databases
Genome annotation databases
|UCSC||RGD:620795. rat. |
|RGD||620795. Src. |
Enzyme and pathway databases
|Reactome||REACT_114732. Cell-Cell communication. |
Gene expression databases
|GermOnline||ENSRNOG00000009495. Rattus norvegicus. |
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||SSF56112. Kinase_like. 1 hit. |
SSF50044. SH3. 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: Q9WUD9|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families