Q9WUD9 (SRC_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Proto-oncogene tyrosine-protein kinase Src
EC=2.7.10.2

Alternative name(s):
Proto-oncogene c-Src
pp60c-src
Short name=p60-Src

Gene names

Name:

Src

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	536 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	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
Subunit structure	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
Subcellular location	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.
Post-translational modification	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.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Biological process	Cell adhesion Cell cycle Immunity
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane Mitochondrion Mitochondrion inner membrane Nucleus
Disease	Proto-oncogene
Domain	SH2 domain SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Myristate Phosphoprotein S-nitrosylation Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of protein kinase B activity Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB adherens junction organization Inferred from direct assay PubMed 15389520. Source: RGD bone resorption Inferred from sequence or structural similarity. Source: UniProtKB cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell proliferation Inferred from direct assay PubMed 15856020. Source: RGD cell-cell adhesion Inferred from expression pattern PubMed 15591141. Source: RGD cellular response to fatty acid Inferred from expression pattern PubMed 20149623. Source: RGD cellular response to hypoxia Inferred from expression pattern PubMed 20380727. Source: RGD cellular response to insulin stimulus Inferred from expression pattern PubMed 19952103. Source: RGD cellular response to lipopolysaccharide Inferred from expression pattern PubMed 20149623. Source: RGD cellular response to progesterone stimulus Inferred from mutant phenotype PubMed 21440892. Source: BHF-UCL epidermal growth factor receptor signaling pathway Inferred from expression pattern PubMed 15856020. Source: RGD negative regulation of focal adhesion assembly Inferred from mutant phenotype PubMed 21440892. Source: BHF-UCL negative regulation of transcription, DNA-dependent Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB nerve growth factor receptor signaling pathway Inferred from direct assay PubMed 15546918. Source: RGD peptidyl-serine phosphorylation Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB platelet-derived growth factor receptor signaling pathway Inferred from expression pattern PubMed 12819032. Source: RGD positive regulation of DNA biosynthetic process Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of MAP kinase activity Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of apoptotic process Inferred from direct assay PubMed 15322113. Source: RGD positive regulation of cell adhesion Inferred from direct assay Ref.7. Source: RGD positive regulation of cyclin-dependent protein kinase activity Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of cytokine secretion Inferred from mutant phenotype PubMed 19736311. Source: RGD positive regulation of glucose metabolic process Inferred from mutant phenotype PubMed 19230846. Source: RGD positive regulation of insulin receptor signaling pathway Inferred from direct assay PubMed 14985360. Source: RGD positive regulation of phosphatidylinositol 3-kinase activity Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of platelet-derived growth factor receptor signaling pathway Inferred from expression pattern PubMed 16530387. Source: UniProtKB positive regulation of protein autophosphorylation Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB positive regulation of smooth muscle cell migration Inferred from mutant phenotype PubMed 19736311. Source: RGD positive regulation of transcription, DNA-dependent Inferred from mutant phenotype PubMed 16530387. Source: UniProtKB progesterone receptor signaling pathway Inferred from mutant phenotype PubMed 21440892. Source: BHF-UCL protein autophosphorylation Inferred from direct assay PubMed 16530387. Source: UniProtKB response to acid Inferred from expression pattern PubMed 12081562. Source: RGD response to drug Inferred from expression pattern PubMed 20149623. Source: RGD response to electrical stimulus Inferred from expression pattern PubMed 20356829. Source: RGD response to hydrogen peroxide Inferred from expression pattern PubMed 12226102. Source: RGD response to mechanical stimulus Inferred from expression pattern PubMed 15731459. Source: RGD response to mineralocorticoid stimulus Inferred from expression pattern PubMed 16157790. Source: RGD response to nutrient levels Inferred from expression pattern PubMed 20357031. Source: RGD response to virus Inferred from expression pattern PubMed 20333648. Source: RGD transcytosis Inferred from direct assay PubMed 15007081. Source: RGD
Cellular_component	caveola Inferred from direct assay PubMed 20167931. Source: RGD cytosol Non-traceable author statement PubMed 16530387. Source: UniProtKB mitochondrial inner membrane Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell postsynaptic density Inferred from direct assay PubMed 20356829. Source: RGD
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW heme binding Inferred from sequence or structural similarity. Source: UniProtKB non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein tyrosine kinase activity Inferred from direct assay PubMed 12488346. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 536	536	Proto-oncogene tyrosine-protein kinase Src		PRO_0000088143
Regions
	Domain	84 – 145	62	SH3
	Domain	151 – 248	98	SH2
	Domain	270 – 523	254	Protein kinase
	Nucleotide binding	276 – 284	9	ATP By similarity
Sites
	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

Sequences

	Sequence		Length	Mass (Da)
	Q9WUD9 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 302A22AF357890F8	FASTA	536	60,078
	10 20 30 40 50 60 MGSNKSKPKD ASQRRRSLEP AENVHGAGGA FPASQTPSKP ASADGHRGPN AAFVPPAAAE 70 80 90 100 110 120 PKLFGGFNSS DTVTSPQRAG PLAGGVTTFV ALYDYESRTE TDLSFKKGER LQIVNNTEGD 130 140 150 160 170 180 WWLAHSLSTG QTGYIPSNYV APFDSIQAEE WYFGKITRRE SERLLLNAEN PRGTFLVRES 190 200 210 220 230 240 ETTKGAYCLS VSDFDNAKGL NVKHYKIRKL DSGGFYITSR TQFNSLQQLV AYYSKHADGL 250 260 270 280 290 300 CHRLTTVCPT SKPQTQGLAK DAWEIPRESL RLEVKLGQGC FGEVWMGTWN GTTRVAIKTL 310 320 330 340 350 360 KPGTMSPEAF LQEAQVMKKL RHEKLVQLYA VVSEEPIYIV TEYMNKGSLL DFLKGETGKY 370 380 390 400 410 420 LRLPQLVDMS AQIASGMAYV DRMNYVHRDL RAANILVGEN LVCKVADFGL ARLIEDNEYT 430 440 450 460 470 480 ARQGAKFPIK WTAPEAALYG RFTIKSDVWS FGILLTELTT KGRVPYPGMV NREVLDQVER 490 500 510 520 530 GYRMPCPPEC PESLHDLMCQ CWRKEPEERP TFEYLQAFLE DYFTSTERQY QPGENL

References

[1]	"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]. Strain: Sprague-Dawley. Tissue: Testis.
[2]	"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.
[3]	"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.
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF130457 mRNA. Translation: AAD24180.1.
IPI	IPI00200886.
UniGene	Rn.112600.
3D structure databases
ProteinModelPortal	Q9WUD9.
SMR	Q9WUD9. Positions 86-536.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-42731N.
MINT	MINT-1488989.
PTM databases
PhosphoSite	Q9WUD9.
Proteomic databases
PaxDb	Q9WUD9.
PRIDE	Q9WUD9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
UCSC	RGD:620795. rat.
Organism-specific databases
RGD	620795. Src.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233858.
HOVERGEN	HBG008761.
InParanoid	Q9WUD9.
Enzyme and pathway databases
Reactome	REACT_114732. Cell-Cell communication.
Gene expression databases
ArrayExpress	Q9WUD9.
Genevestigator	Q9WUD9.
GermOnline	ENSRNOG00000009495. Rattus norvegicus.
Family and domain databases
Gene3D	3.30.505.10. 1 hit.
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR000980. SH2. IPR001452. SH3_domain. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00017. SH2. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PRINTS	PR00401. SH2DOMAIN. PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00252. SH2. 1 hit. SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
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. [Graphical view]
ProtoNet	Search...
Other
BindingDB	Q9WUD9.
ChEMBL	CHEMBL3014.

Entry information

Entry name

SRC_RAT

Accession

Primary (citable) accession number: Q9WUD9

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 119 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program