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Protein

Neuronal proto-oncogene tyrosine-protein kinase Src

Gene

Src

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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) (By similarity). 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 (PubMed:9344858). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation (By similarity). 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 (By similarity). 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:14739300). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). 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. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-226'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Involved in anchorage-independent cell growth (By similarity). Required for podosome formation (PubMed:21525037).By similarity3 Publications5 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation1 Publication

Enzyme regulationi

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.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei303ATPPROSITE-ProRule annotation1
Active sitei394Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi281 – 289ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processCell adhesion, Cell cycle, Immunity
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.2 3474
ReactomeiR-MMU-1227986 Signaling by ERBB2
R-MMU-1257604 PIP3 activates AKT signaling
R-MMU-1295596 Spry regulation of FGF signaling
R-MMU-1433557 Signaling by SCF-KIT
R-MMU-1433559 Regulation of KIT signaling
R-MMU-177929 Signaling by EGFR
R-MMU-180292 GAB1 signalosome
R-MMU-186763 Downstream signal transduction
R-MMU-191647 c-src mediated regulation of Cx43 function and closure of gap junctions
R-MMU-2029481 FCGR activation
R-MMU-354192 Integrin alphaIIb beta3 signaling
R-MMU-354194 GRB2:SOS provides linkage to MAPK signaling for Integrins
R-MMU-372708 p130Cas linkage to MAPK signaling for integrins
R-MMU-389356 CD28 co-stimulation
R-MMU-389513 CTLA4 inhibitory signaling
R-MMU-3928662 EPHB-mediated forward signaling
R-MMU-3928663 EPHA-mediated growth cone collapse
R-MMU-3928664 Ephrin signaling
R-MMU-3928665 EPH-ephrin mediated repulsion of cells
R-MMU-418592 ADP signalling through P2Y purinoceptor 1
R-MMU-418885 DCC mediated attractive signaling
R-MMU-430116 GP1b-IX-V activation signalling
R-MMU-437239 Recycling pathway of L1
R-MMU-4420097 VEGFA-VEGFR2 Pathway
R-MMU-456926 Thrombin signalling through proteinase activated receptors (PARs)
R-MMU-5218921 VEGFR2 mediated cell proliferation
R-MMU-5607764 CLEC7A (Dectin-1) signaling
R-MMU-5663220 RHO GTPases Activate Formins
R-MMU-5673000 RAF activation
R-MMU-5674135 MAP2K and MAPK activation
R-MMU-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-MMU-69231 Cyclin D associated events in G1
R-MMU-8853659 RET signaling
R-MMU-8874081 MET activates PTK2 signaling
R-MMU-8934903 Receptor Mediated Mitophagy
R-MMU-8941858 Regulation of RUNX3 expression and activity

Names & Taxonomyi

Protein namesi
Recommended name:
Neuronal proto-oncogene tyrosine-protein kinase Src (EC:2.7.10.21 Publication)
Alternative name(s):
Proto-oncogene c-Src
pp60c-src
Short name:
p60-Src
Gene namesi
Name:Src
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 2

Organism-specific databases

MGIiMGI:98397 Src

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Cytoskeleton, Membrane, Mitochondrion, Mitochondrion inner membrane, Nucleus

Pathology & Biotechi

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL3074

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000881422 – 541Neuronal proto-oncogene tyrosine-protein kinase SrcAdd BLAST540

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycineBy similarity1
Modified residuei17PhosphoserineCombined sources1
Modified residuei21PhosphoserineCombined sources1
Modified residuei74PhosphoserineCombined sources1
Modified residuei192PhosphotyrosineCombined sources1
Modified residuei424Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei424Phosphotyrosine; by FAK2By similarity1
Modified residuei535Phosphotyrosine; by CSKBy similarity1

Post-translational modificationi

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).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).By similarity

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiP05480
PaxDbiP05480
PeptideAtlasiP05480
PRIDEiP05480

PTM databases

iPTMnetiP05480
PhosphoSitePlusiP05480

Expressioni

Gene expression databases

BgeeiENSMUSG00000027646
CleanExiMM_SRC
ExpressionAtlasiP05480 baseline and differential
GenevisibleiP05480 MM

Interactioni

Subunit structurei

Interacts with CDCP1, PELP1, TGFB1I1 and TOM1L2 (By similarity). Interacts with DDEF1/ASAP1 via its SH3 domain (PubMed:9819391). Interacts with CCPG1 (PubMed:17000758). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (By similarity). Interacts with RALGPS1 via its SH3 domain (By similarity). Interacts with CAV2 (tyrosine phosphorylated form) (By similarity). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with FCAMR and PXN (By similarity). Interacts with ARRB2 (PubMed:19122674). Interacts with ARRB1 (By similarity). Interacts with SRCIN1 (By similarity). Interacts with NDFIP2 and more weakly with NDFIP1 (By similarity). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1, ESR1 (dimethylated on arginine) and FAK (PubMed:14739300). Interacts (via SH2 and SH3 domain) with TNK2 (By similarity). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (By similarity). Interacts with TRAF3 (via RING-type zinc finger domain) (By similarity). Interacts with DDX58, MAVS and TBK1 (By similarity). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (By similarity). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14739300). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (PubMed:16684964). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (PubMed:11433297). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with ERBB2 and STAT1 (PubMed:7542762, PubMed:9344858). Interacts with PDGFRA (tyrosine phosphorylated) (PubMed:14644164). Interacts with CSF1R (PubMed:7681396). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (By similarity). Interacts with DDR2 (By similarity). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (By similarity). Interacts with DDR1 and DAB2 (PubMed:20093046). Interacts with TRAP1 (By similarity). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at 'Tyr-424' (By similarity). Interacts with ARHGEF5 (PubMed:21525037). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (By similarity). Interacts with MPP2 (By similarity). Interacts with PRR7 (By similarity). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (By similarity).By similarity13 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi203491, 44 interactors
CORUMiP05480
DIPiDIP-31071N
IntActiP05480, 44 interactors
MINTiP05480
STRINGi10090.ENSMUSP00000090237

Chemistry databases

BindingDBiP05480

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
6F3FX-ray2.42A85-541[»]
ProteinModelPortaliP05480
SMRiP05480
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini83 – 150SH3PROSITE-ProRule annotationAdd BLAST68
Domaini156 – 253SH2PROSITE-ProRule annotationAdd BLAST98
Domaini275 – 528Protein kinasePROSITE-ProRule annotationAdd BLAST254

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily.PROSITE-ProRule annotation

Keywords - Domaini

SH2 domain, SH3 domain

Phylogenomic databases

eggNOGiKOG0197 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118938
HOGENOMiHOG000233858
HOVERGENiHBG008761
InParanoidiP05480
KOiK05704
OMAiCQCWRKD
OrthoDBiEOG091G0D46

Family and domain databases

Gene3Di3.30.505.10, 1 hit
InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR000980 SH2
IPR036860 SH2_dom_sf
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
PF00017 SH2, 1 hit
PF00018 SH3_1, 1 hit
PRINTSiPR00401 SH2DOMAIN
PR00452 SH3DOMAIN
PR00109 TYRKINASE
SMARTiView protein in SMART
SM00252 SH2, 1 hit
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF50044 SSF50044, 1 hit
SSF55550 SSF55550, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in 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

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P05480-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGSNKSKPKD ASQRRRSLEP SENVHGAGGA FPASQTPSKP ASADGHRGPS
60 70 80 90 100
AAFVPPAAEP KLFGGFNSSD TVTSPQRAGP LAGGVTTFVA LYDYESRTET
110 120 130 140 150
DLSFKKGERL QIVNNTRKVD VREGDWWLAH SLSTGQTGYI PSNYVAPSDS
160 170 180 190 200
IQAEEWYFGK ITRRESERLL LNAENPRGTF LVRESETTKG AYCLSVSDFD
210 220 230 240 250
NAKGLNVKHY KIRKLDSGGF YITSRTQFNS LQQLVAYYSK HADGLCHRLT
260 270 280 290 300
TVCPTSKPQT QGLAKDAWEI PRESLRLEVK LGQGCFGEVW MGTWNGTTRV
310 320 330 340 350
AIKTLKPGTM SPEAFLQEAQ VMKKLRHEKL VQLYAVVSEE PIYIVTEYMN
360 370 380 390 400
KGSLLDFLKG ETGKYLRLPQ LVDMSAQIAS GMAYVERMNY VHRDLRAANI
410 420 430 440 450
LVGENLVCKV ADFGLARLIE DNEYTARQGA KFPIKWTAPE AALYGRFTIK
460 470 480 490 500
SDVWSFGILL TELTTKGRVP YPGMVNREVL DQVERGYRMP CPPECPESLH
510 520 530 540
DLMCQCWRKE PEERPTFEYL QAFLEDYFTS TEPQYQPGEN L
Length:541
Mass (Da):60,645
Last modified:July 27, 2011 - v4
Checksum:i0534AF027783BCCF
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti80P → A in AAA40135 (PubMed:2440106).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M17031 mRNA Translation: AAA40135.1
AY902331 Genomic DNA Translation: AAX90616.1
AL672259 Genomic DNA Translation: CAM16141.1
CH466551 Genomic DNA Translation: EDL06234.1
CCDSiCCDS38305.1
PIRiA43610
RefSeqiNP_001020566.1, NM_001025395.2
NP_033297.2, NM_009271.3
UniGeneiMm.22845

Genome annotation databases

EnsembliENSMUST00000092576; ENSMUSP00000090237; ENSMUSG00000027646
ENSMUST00000109529; ENSMUSP00000105155; ENSMUSG00000027646
GeneIDi20779
KEGGimmu:20779
UCSCiuc008npa.1 mouse

Similar proteinsi

Entry informationi

Entry nameiSRC_MOUSE
AccessioniPrimary (citable) accession number: P05480
Secondary accession number(s): Q2M4I4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1988
Last sequence update: July 27, 2011
Last modified: June 20, 2018
This is version 202 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

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