Proto-oncogene tyrosine-protein kinase Src

This article is about the kinase c-Src, for the kinase that phosphorylates c-Src, see CSK.

Proto-oncogene tyrosine-protein kinase Src, also known as proto-oncogene c-Src, or simply c-Src (cellular Src; pronounced "sarc", as it is short for sarcoma), is a non-receptor tyrosine kinase protein that in humans is encoded by the SRC gene. It belongs to a family of Src family kinases and is similar to the v-Src (viral Src) gene of Rous sarcoma virus. It includes an SH2 domain, an SH3 domain and a tyrosine kinase domain. Two transcript variants encoding the same protein have been found for this gene.^[5]

SRC
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1A07, 1A08, 1A09, 1A1A, 1A1B, 1A1C, 1A1E, 1FMK, 1HCS, 1HCT, 1KSW, 1O41, 1O42, 1O43, 1O44, 1O45, 1O46, 1O47, 1O48, 1O49, 1O4A, 1O4B, 1O4C, 1O4D, 1O4E, 1O4F, 1O4G, 1O4H, 1O4I, 1O4J, 1O4K, 1O4L, 1O4M, 1O4N, 1O4O, 1O4P, 1O4Q, 1O4R, 1SHD, 1Y57, 1YI6, 1YOJ, 1YOL, 1YOM, 2BDF, 2H8H, 3VRO, 3ZMP, 3ZMQ, 4F59, 4F5A, 4F5B, 4HXJ, 4K11, 4MXO, 4MXX, 4MXY, 4MXZ
Identifiers
Aliases	SRC, ASV, SRC1, c-p60-Src, SRC proto-oncogene, non-receptor tyrosine kinase, THC6
External IDs	OMIM: 190090 MGI: 98397 HomoloGene: 21120 GeneCards: SRC
EC number	2.7.10.2
Gene location (Human) Chr. Chromosome 20 (human)^[1] Band 20q11.23 Start 37,344,685 bp^[1] End 37,406,050 bp^[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)^[2] Band 2 H1|2 78.35 cM Start 157,418,444 bp^[2] End 157,471,862 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in body of stomach gallbladder rectum body of pancreas transverse colon ganglionic eminence gastric mucosa ascending aorta canal of the cervix left adrenal gland Top expressed in external carotid artery superior frontal gyrus internal carotid artery molar aortic valve ascending aorta jejunum medial geniculate nucleus ganglionic eminence yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transmembrane transporter binding protein domain specific binding protein-containing complex binding SH2 domain binding kinase activity signaling receptor binding estrogen receptor binding ATP binding protein kinase activity insulin receptor binding non-membrane spanning protein tyrosine kinase activity kinase binding heme binding enzyme binding transferase activity ephrin receptor binding scaffold protein binding integrin binding protein binding protein kinase binding cell adhesion molecule binding protein kinase C binding hormone receptor binding nucleotide binding growth factor receptor binding phosphoprotein binding protein tyrosine kinase activity protein C-terminus binding ubiquitin protein ligase binding cadherin binding connexin binding phosphatidylinositol-4,5-bisphosphate 3-kinase activity Cellular component cytoplasm cytosol membrane extrinsic component of cytoplasmic side of plasma membrane ruffle membrane mitochondrion perinuclear region of cytoplasm caveola neuron projection cytoskeleton nucleus lysosome extracellular exosome late endosome plasma membrane actin filament postsynaptic density mitochondrial inner membrane podosome nucleoplasm glutamatergic synapse postsynaptic specialization, intracellular component Biological process response to mineralocorticoid negative regulation of telomere maintenance via telomerase response to interleukin-1 positive regulation of MAP kinase activity positive regulation of canonical Wnt signaling pathway negative regulation of telomerase activity cellular response to progesterone stimulus regulation of intracellular estrogen receptor signaling pathway stress fiber assembly positive regulation of protein serine/threonine kinase activity platelet activation positive regulation of smooth muscle cell migration protein phosphorylation regulation of vascular permeability vascular endothelial growth factor receptor signaling pathway positive regulation of ERK1 and ERK2 cascade regulation of podosome assembly cell cycle substrate adhesion-dependent cell spreading osteoclast development cell population proliferation transforming growth factor beta receptor signaling pathway cellular response to hypoxia cellular response to transforming growth factor beta stimulus negative regulation of protein homooligomerization positive regulation of protein kinase B signaling positive regulation of lamellipodium morphogenesis epidermal growth factor receptor signaling pathway branching involved in mammary gland duct morphogenesis Fc-gamma receptor signaling pathway involved in phagocytosis negative regulation of intrinsic apoptotic signaling pathway negative regulation of extrinsic apoptotic signaling pathway response to mechanical stimulus response to virus positive regulation of epithelial cell migration signal complex assembly stimulatory C-type lectin receptor signaling pathway positive regulation of platelet-derived growth factor receptor signaling pathway oogenesis positive regulation of transcription, DNA-templated regulation of epithelial cell migration response to nutrient levels positive regulation of DNA biosynthetic process cellular response to insulin stimulus protein autophosphorylation viral process negative regulation of focal adhesion assembly response to acidic pH response to fatty acid regulation of cell projection assembly phosphorylation immune system process negative regulation of mitochondrial depolarization positive regulation of integrin activation negative regulation of apoptotic process cellular response to platelet-derived growth factor stimulus positive regulation of podosome assembly positive regulation of glucose metabolic process transcytosis cellular response to fluid shear stress response to electrical stimulus positive regulation of protein transport uterus development protein destabilization regulation of cell-cell adhesion peptidyl-tyrosine autophosphorylation integrin-mediated signaling pathway positive regulation of insulin receptor signaling pathway progesterone receptor signaling pathway negative regulation of transcription, DNA-templated adherens junction organization negative regulation of anoikis response to hydrogen peroxide leukocyte migration activation of protein kinase B activity negative regulation of cysteine-type endopeptidase activity involved in apoptotic process intracellular signal transduction regulation of early endosome to late endosome transport ephrin receptor signaling pathway T cell costimulation positive regulation of intracellular signal transduction regulation of caveolin-mediated endocytosis regulation of cell cycle positive regulation of phosphatidylinositol 3-kinase activity cellular response to reactive oxygen species cellular response to peptide hormone stimulus positive regulation of gene expression cellular response to fatty acid regulation of cell population proliferation angiotensin-activated signaling pathway involved in heart process peptidyl-serine phosphorylation positive regulation of protein autophosphorylation positive regulation of cyclin-dependent protein serine/threonine kinase activity positive regulation of apoptotic process forebrain development regulation of protein binding cellular response to lipopolysaccharide regulation of bone resorption cell migration signal transduction positive regulation of cell adhesion cell adhesion positive regulation of protein processing innate immune response positive regulation of peptidyl-tyrosine phosphorylation neurotrophin TRK receptor signaling pathway positive regulation of small GTPase mediated signal transduction bone resorption central nervous system development positive regulation of protein localization to nucleus platelet-derived growth factor receptor signaling pathway ERBB2 signaling pathway intracellular estrogen receptor signaling pathway axon guidance macroautophagy peptidyl-tyrosine phosphorylation entry of bacterium into host cell cell-cell adhesion primary ovarian follicle growth positive regulation of ovarian follicle development transmembrane receptor protein tyrosine kinase signaling pathway positive regulation of phosphatidylinositol 3-kinase signaling cell differentiation phosphatidylinositol phosphate biosynthetic process regulation of postsynaptic neurotransmitter receptor activity positive regulation of non-membrane spanning protein tyrosine kinase activity G protein-coupled receptor signaling pathway cellular response to hydrogen peroxide positive regulation of platelet-derived growth factor receptor-beta signaling pathway odontogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6714 20779 Ensembl ENSG00000197122 ENSMUSG00000027646 UniProt P12931 P05480 RefSeq (mRNA) NM_005417 NM_198291 NM_001025395 NM_009271 RefSeq (protein) NP_005408 NP_938033 NP_001020566 NP_033297 Location (UCSC) Chr 20: 37.34 – 37.41 Mb Chr 2: 157.42 – 157.47 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

c-Src phosphorylates specific tyrosine residues in other tyrosine kinases. It plays a role in the regulation of embryonic development and cell growth. An elevated level of activity of c-Src is suggested to be linked to cancer progression by promoting other signals.^[6] Mutations in c-Src could be involved in the malignant progression of colon cancer. c-Src should not be confused with CSK (C-terminal Src kinase), an enzyme that phosphorylates c-Src at its C-terminus and provides negative regulation of Src's enzymatic activity.

c-Src was originally discovered by American scientists J. Michael Bishop and Harold E. Varmus, for which they were awarded the 1989 Nobel Prize in Physiology or Medicine.^[7]

Discovery

In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens possess a gene that is structurally closely related to v-Src.^[8] The normal cellular gene was called c-src (cellular-src).^[9] This discovery changed the current thinking about cancer from a model wherein cancer is caused by a foreign substance (a viral gene) to one where a gene that is normally present in the cell can cause cancer. It is believed that at one point an ancestral virus mistakenly incorporated the c-Src gene of its cellular host. Eventually this normal gene mutated into an abnormally functioning oncogene within the Rous sarcoma virus. Once the oncogene is transfected back into a chicken, it can lead to cancer.

Structure

There are 9 members of the Src family kinases: c-Src, Yes, Fyn, Fgr, Yrk, Lyn, Blk, Hck, and Lck.^[10] The expression of these Src family members are not the same throughout all tissues and cell types. Src, Fyn and Yes are expressed ubiquitously in all cell types while the others are generally found in hematopoietic cells.^{[11][12][13][14]}

c-Src is made up of 6 functional regions: Src homology 4 domain (SH4 domain), unique region, SH3 domain, SH2 domain, catalytic domain and short regulatory tail.^[15] When Src is inactive, the phosphorylated tyrosine group at the 527 position interacts with the SH2 domain which helps the SH3 domain interact with the flexible linker domain and thereby keeps the inactive unit tightly bound. The activation of c-Src causes the dephosphorylation of the tyrosine 527. This induces long-range allostery via protein domain dynamics, causing the structure to be destabilized, resulting in the opening up of the SH3, SH2 and kinase domains and the autophosphorylation of the residue tyrosine 416.^[16][17][18]

The autophosphorylation of Y416 as well as phosphorylation of selected Src substrates is enhanced through dimerization of c-Src.^[19] The dimerization of c-Src is mediated by the interaction of the myristoylated N-terminal region of one partner and the kinase domain of another partner.^[19] Both the N-terminally attached myristic acid and the peptide sequences of the unique region are involved in the interaction.^[19] Given the versatility inherent in this intrinsically disordered region, its multisite phosphorylations, and its divergence within the family, the unique domain likely functions as a central signaling hub overseeing much of the enzymatic activities and unique functions of Src family kinases.^[19]

c-Src can be activated by many transmembrane proteins that include: adhesion receptors, receptor tyrosine kinases, G-protein coupled receptors and cytokine receptors. Most studies have looked at the receptor tyrosine kinases and examples of these are platelet derived growth factor receptor (PDGFR) pathway and epidermal growth factor receptor (EGFR).

Src contains at least three flexible protein domains, which, in conjunction with myristoylation, can mediate attachment to membranes and determine subcellular localization.^[20]

Function

This proto-oncogene may play a role in the regulation of embryonic development and cell growth.

When src is activated, it promotes survival, angiogenesis, proliferation and invasion pathways. It also regulates angiogenic factors and vascular permeability after focal cerebral ischemia-reperfusion,^[21][22] and regulates matrix metalloproteinase-9 activity after intracerebral hemorrhage.^[23]

Role in cancer

The activation of the c-Src pathway has been observed in about 50% of tumors from colon, liver, lung, breast and the pancreas.^[24] Since the activation of c-Src leads to the promotion of survival, angiogenesis, proliferation and invasion pathways, the aberrant growth of tumors in cancers is observed. A common mechanism is that there are genetic mutations that result in the increased activity or the overexpression of the c-Src leading to the constant activation of the c-Src.

Colon cancer

The activity of c-Src has been best characterized in colon cancer. Researchers have shown that Src expression is 5 to 8 fold higher in premalignant polyps than normal mucosa.^[25][26][27] The elevated c-Src levels have also been shown to have a correlation with advanced stages of the tumor, size of tumor, and metastatic potential of tumors.^[28][29]

Breast cancer

EGFR activates c-Src while EGF also increases the activity of c-Src. In addition, overexpression of c-Src increases the response of EGFR-mediated processes. So both EGFR and c-Src enhance the effects of one another. Elevated expression levels of c-Src were found in human breast cancer tissues compared to normal tissues.^[30][31][32]

Overexpression of Human Epidermal Growth Factor Receptor 2 (HER2), also known as erbB2, is correlated with a worse prognosis for breast cancer.^[33][34] Thus, c-Src plays a key role in the tumor progression of breast cancers.

Prostate cancer

Members of the Src family kinases Src, Lyn and Fgr are highly expressed in malignant prostate cells compared to normal prostate cells.^[35] When the primary prostate cells are treated with KRX-123, which is an inhibitor of Lyn, the cells in vitro were reduced in proliferation, migration and invasive potential.^[36] So the use of a tyrosine kinase inhibitor is a possible way of reducing the progression of prostate cancers.

As a drug target

A number of tyrosine kinase inhibitors that target c-Src tyrosine kinase (as well as related tyrosine kinases) have been developed for therapeutic use.^[37] One notable example is dasatinib which has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (PH+) acute lymphocytic leukemia (ALL).^[38] Dasatinib is also in clinical trials for the use in non-Hodgkin’s lymphoma, metastatic breast cancer and prostate cancer. Other tyrosine kinase inhibitor drugs that are in clinical trials include bosutinib,^[39] bafetinib, AZD-0530, XLl-999, KX01 and XL228.^[6] HSP90 inhibitor NVP-BEP800 has been described to affect stability of Src tyrosine kinase and growth of T-cell and B-cell acute lymphoblastic leukemias. ^[40]

Interactions

Src (gene) has been shown to interact with the following signaling pathways:

Survival

• PI3K
• Akt
• IKK
• NFkB
• Caspase 9

Angiogenesis

• STAT3
• p38 MAPK
• VEGF
• IL-8

Proliferation

• Shc
• Grb2/SOS
• Ras
• Raf
• MEK1 / MEK2
• Erk1/2

Motility

• FAK
• p190Rho/GAP
• Paxillin
• p130CAS
• RhoA
• JNK
• c-jun
• MLCK
• Myosin

Additional images

Overview of signal transduction pathways involved in apoptosis.

l i p i d - b i n d i n g P h o s p h o s e r i n e P h o s p h o s e r i n e SH3 S p l i c i n g v a r i a n t SH2 V a r i a n t P h o s p h o t y r o s i n e h y d r o p h o b i c b i n d i n g p o c k e t V a r i a n t Tyrosine kinase A c t i v e s i t e S H 3 / S H 2 d o m a i n i n t e r f a c e A T P P r o t o n a c c e p t o r a c t i v a t i o n l o o p P h o s p h o t y r o s i n e S - n i t r o s o c y s t e i n e P h o s p h o t h r e o n i n e P h o s p h o t y r o s i n e P h o s p h o t y r o s i n e P S / P T / P S ( C D K 5 ) P h o s p h o t y r F A K 2 / a u t o s w a p p e d d i m e r / p e p t i d e b i n d a u t o i n h i b i t o r y p T y r Top row:    Beta-strand region    Hydrogen bonded turn    Helical region site 2 2 lipid-binding site 17 17 Phosphoserine site 35 35 Phosphoserine site 69 69 Phosphoserine site 74 74 Phosphothreonine site 75 75 Phosphoserine; by CDK5 region 87 93 Beta-strand region region 88 143 SH3 site 88 88 swapped dimer interface [polypeptide binding] site 93 93 peptide ligand binding site [polypeptide binding] region 99 102 Beta-strand region region 110 114 Beta-strand region region 117 117 Splicing variant region 118 126 Beta-strand region region 127 129 Hydrogen bonded turn region 132 136 Beta-strand region region 137 139 Helical region region 140 142 Beta-strand region region 146 148 Helical region region 147 247 SH2 region 152 154 Beta-strand region site 158 158 autoinhibitory site [polypeptide binding] site 158 158 phosphotyrosine binding pocket [polypeptide binding] region 158 165 Helical region region 167 170 Beta-strand region region 174 179 Beta-strand region region 176 176 Variant region 181 183 Beta-strand region region 187 195 Beta-strand region site 187 187 Phosphotyrosine (By similarity) region 196 198 Hydrogen bonded turn region 199 209 Beta-strand region site 205 205 hydrophobic binding pocket [polypeptide binding] region 211 213 Beta-strand region region 215 218 Beta-strand region region 221 225 Beta-strand region region 226 233 Helical region region 237 237 Variant region 240 242 Beta-strand region region 256 259 Beta-strand region region 267 269 Helical region region 270 519 Tyrosine kinase region 270 278 Beta-strand region site 276 276 Active site (ATP binding) region 283 289 Beta-strand region site 290 290 SH3/SH2 domain interface [polypeptide binding] region 290 292 Hydrogen bonded turn region 293 299 Beta-strand region site 298 298 ATP region 302 304 Hydrogen bonded turn region 307 319 Helical region region 328 332 Beta-strand region region 334 336 Beta-strand region region 338 341 Beta-strand region region 349 353 Helical region region 355 358 Helical region region 363 382 Helical region site 389 389 Proton acceptor region 392 394 Helical region region 395 397 Beta-strand region region 399 401 Helical region region 403 405 Beta-strand region site 406 406 activation loop (A-loop) region 410 413 Helical region region 417 420 Helical region site 419 419 Phosphotyrosine; by autocatalysis; alternate site 419 419 Phosphotyrosine; by FAK2; alternate (By similarity) region 423 426 Hydrogen bonded turn region 429 431 Helical region region 434 439 Helical region site 439 439 Phosphotyrosine region 444 459 Helical region region 460 462 Hydrogen bonded turn region 471 479 Helical region region 492 501 Helical region site 501 501 S-nitrosocysteine (By similarity) region 506 508 Helical region site 511 511 Phosphothreonine region 512 520 Helical region region 521 523 Hydrogen bonded turn site 522 522 Phosphotyrosine site 530 530 Phosphotyrosine; by CSK

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External links

• src+Gene at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• src-Family+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Proteopedia SRC - interactive 3D model of the structure of SRC
• Vega geneview
• Info with links in the Cell Migration Gateway 2014-12-11 at the Wayback Machine
• Overview of all the structural information available in the PDB for UniProt: P12931 (Proto-oncogene tyrosine-protein kinase Src) at the PDBe-KB.