InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: SRC

Summary

InnateDB Protein

IDBP-74093.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

SRC

Protein Name

v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)

Synonyms

ASV; c-SRC; p60-Src; SRC1;

Species

Homo sapiens

Ensembl Protein

ENSP00000362659

InnateDB Gene

IDBG-74081 (SRC)

Protein Structure

UniProt Annotation

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-731'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr- 128'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. {ECO:0000269PubMed:11389730, ECO:0000269PubMed:12615910, ECO:0000269PubMed:14585963, ECO:0000269PubMed:16186108, ECO:0000269PubMed:18586953, ECO:0000269PubMed:19419966, ECO:0000269PubMed:20100835, ECO:0000269PubMed:20525694, ECO:0000269PubMed:21309750, ECO:0000269PubMed:21411625, ECO:0000269PubMed:22710723, ECO:0000269PubMed:2498394, ECO:0000269PubMed:3093483, ECO:0000269PubMed:7853507, ECO:0000269PubMed:8755529, ECO:0000269PubMed:8759729}.

Subcellular Localization

Cell membrane. Mitochondrion inner membrane. Nucleus. Cytoplasm, cytoskeleton. Note=Localizes to focal adhesion sites following integrin engagement. Localization to focal adhesion sites requires myristoylation and the SH3 domain.

Disease Associations

Note=SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.

Tissue Specificity

Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 446 experimentally validated interaction(s) in this database.
They are also associated with 46 interaction(s) predicted by orthology.

Experimentally validated
Total	446 [view]
Protein-Protein	443 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	46 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004715	non-membrane spanning protein tyrosine kinase activity
GO:0005070	SH3/SH2 adaptor activity
GO:0005102	receptor binding
GO:0005178	integrin binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0020037	heme binding
GO:0042169	SH2 domain binding
GO:0044325	ion channel binding
GO:0046875	ephrin receptor binding
GO:0051219	phosphoprotein binding
GO:0070851	growth factor receptor binding

Biological Process

GO:0006468	protein phosphorylation
GO:0007049	cell cycle
GO:0007155	cell adhesion
GO:0007165	signal transduction
GO:0007172	signal complex assembly
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007265	Ras protein signal transduction
GO:0007411	axon guidance
GO:0007596	blood coagulation
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0016032	viral process
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0030168	platelet activation
GO:0031295	T cell costimulation
GO:0032463	negative regulation of protein homooligomerization
GO:0033625	positive regulation of integrin activation
GO:0035556	intracellular signal transduction
GO:0038096	Fc-gamma receptor signaling pathway involved in phagocytosis
GO:0043066	negative regulation of apoptotic process
GO:0043114	regulation of vascular permeability
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0045124	regulation of bone resorption
GO:0045453	bone resorption
GO:0046777	protein autophosphorylation
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0050847	progesterone receptor signaling pathway
GO:0050900	leukocyte migration
GO:0051895	negative regulation of focal adhesion assembly
GO:0051897	positive regulation of protein kinase B signaling
GO:0051902	negative regulation of mitochondrial depolarization
GO:0061024	membrane organization
GO:0070555	response to interleukin-1
GO:0071393	cellular response to progesterone stimulus
GO:2000811	negative regulation of anoikis
GO:2001237	negative regulation of extrinsic apoptotic signaling pathway
GO:2001243	negative regulation of intrinsic apoptotic signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005743	mitochondrial inner membrane
GO:0005764	lysosome
GO:0005770	late endosome
GO:0005829	cytosol
GO:0005856	cytoskeleton
GO:0005886	plasma membrane
GO:0005901	caveola
GO:0070062	extracellular vesicular exosome

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000980 SH2 domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR001452 SH3 domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR011511 Variant SH3 domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM