Src (gene)
| V-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) | |||||||||||
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File:PBB Protein SRC image.jpg PDB rendering based on 1a07. | |||||||||||
| Identifiers | |||||||||||
| Symbols | SRC ; ASV; SRC1; c-SRC; p60-Src | ||||||||||
| External IDs | Template:OMIM5 Template:MGI HomoloGene: 21120 | ||||||||||
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| RNA expression pattern | |||||||||||
| File:PBB GE SRC 213324 at.png | |||||||||||
| File:PBB GE SRC 221284 s at.png | |||||||||||
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| Orthologs | |||||||||||
| Template:GNF Ortholog box | |||||||||||
| Species | Human | Mouse | |||||||||
| Entrez | n/a | n/a | |||||||||
| Ensembl | n/a | n/a | |||||||||
| UniProt | n/a | n/a | |||||||||
| RefSeq (mRNA) | n/a | n/a | |||||||||
| RefSeq (protein) | n/a | n/a | |||||||||
| Location (UCSC) | n/a | n/a | |||||||||
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Overview
Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus. The discovery of Src family proteins has been instrumental to the modern understanding of cancer as a disease where normally healthy cellular signalling has gone awry.
This gene is highly similar to the v-src gene of Rous sarcoma virus. This proto-oncogene may play a role in the regulation of embryonic development and cell growth. The protein encoded by this gene is a tyrosine-protein kinase whose activity can be inhibited by phosphorylation by c-SRC kinase. Mutations in this gene could be involved in the malignant progression of colon cancer. Two transcript variants encoding the same protein have been found for this gene.[1]
v-src
Francis Peyton Rous was credited with being the first to come up with the idea that viruses could cause cancer. In 1911 he performed an experiment where he removed a type of tumor called a fibrosarcoma from chickens, ground them up, and used centrifugation to remove cells and debris. He injected the remaining liquid into healthy chicks and found that the chicks developed sarcomas. The causative agent in the liquid was later found to be a virus that was called the Rous sarcoma virus (RSV).
Later work by others showed that RSV was a type of retrovirus. Non-cancer-forming retroviruses contain 3 genes, called gag, pol, and env. Some tumor-inducing retroviruses (such as RSV), however, contain a gene called v-src (viral-sarcoma). It was found that the v-src gene in RSV is required for the formation of cancer and that the other genes have no role in oncogenesis.[2]
Src tyrosine kinases transmit integrin-dependent signals central to cell movement and proliferation. Hallmarks of v-src induced transformation are rounding of the cell and the formation of actin rich podosomes on the basal surface of the cell. These structures are correlated with increased invasiveness, a process thought to be essential for metastasis.
v-src lacks the C-terminal inhibitory phosphorylation site (tyrosine-527), and is therefore constitutively active as opposed to normal src (c-src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-src is therefore an instructive example of an oncogene whereas c-src is a proto-oncogene.
c-src
In 1979, J. Michael Bishop and Harold E. Varmus discovered that normal chickens contain a gene that is structurally closely-related to v-src.[2] The normal cellular gene was called c-src (cellular-src).[3] 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. At some point, the normal gene became mutated into an abnormally-functioning oncogene, as is now observed in RSV. Once the oncogene is transfected back into a normal host, it can lead to cancer.
src: The transforming (sarcoma inducing) gene of Rous sarcoma virus. The protein product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase activity (EC 2.7.10.2), that associates with the cytoplasmic face of the plasma membrane. The protein consists of 3 domains, an N-terminal SH3 domain, a central SH2 domain and a Tyrosine kinase domain. The SH2 and SH3 domains cooperate in the auto-inhibition of the kinase domain. c-Src is phosphorylated on an inhibitory tyrosine near the c-terminus of the protein. This produces a binding site for the SH2 domain which, when bound, facilitates binding of the SH3 domain to a low affinity polyproline site within the linker between the SH2 domain and the Kinase domain. Binding of the SH3 domain results in misalignment of residues within the kinase domain's active site inactivating the enzyme. This allows for multiple mechanism for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, as seen in the case of c-Src binding to Focal Adhesion Kinase, or competitive binding of a polyproline binding site to the SH3 domain, as seen in the case of the HIV NEF protein.
Src Family Kinases
The Src family includes nine members: Src, Lck, Hck, Fyn, Blk, Lyn, Fgr, Yes, and Yrk.
See also
External links
- Vega geneview
- src-Family+Kinases at the US National Library of Medicine Medical Subject Headings (MeSH)
- src+Gene at the US National Library of Medicine Medical Subject Headings (MeSH)
References
- ↑ "Entrez Gene: SRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)".
- ↑ 2.0 2.1 Stehelin D, Fujita DJ, Padgett T, Varmus HE, Bishop JM. (1977). "Detection and enumeration of transformation-defective strains of avian sarcoma virus with molecular hybridization". Virology. 76 (2): 675–84. PMID 190771.
- ↑ Oppermann H, Levinson AD, Varmus HE, Levintow L, Bishop JM (1979). "Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src)". Proc Natl Acad Sci U S A. 76 (4): 1804–8. PMID 221907.
- Lodish, Harvey; Burk, Arnold; Zipurksy, Lawrence, et al. "Cancer" in Molecular Cell Biology. 4th edition. 2000. ISBN 0-7167-3706-X. [1]
Further reading
- Frame MC, Fincham VJ, Carragher NO, Wyke JA (2002). "v-Src's hold over actin and cell adhesions". Nat. Rev. Mol. Cell Biol. 3 (4): 233–45. doi:10.1038/nrm779. PMID 11994743.
- Benaim G, Villalobo A (2002). "Phosphorylation of calmodulin. Functional implications". Eur. J. Biochem. 269 (15): 3619–31. PMID 12153558.
- Simeonova PP, Luster MI (2003). "Arsenic carcinogenicity: relevance of c-Src activation". Mol. Cell. Biochem. 234-235 (1–2): 277–82. PMID 12162444.
- Leu TH, Maa MC (2004). "Functional implication of the interaction between EGF receptor and c-Src". Front. Biosci. 8: s28–38. PMID 12456372.
- Greenway AL, Holloway G, McPhee DA; et al. (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. PMID 12734410.
- Dehm SM, Bonham K (2004). "SRC gene expression in human cancer: the role of transcriptional activation". Biochem. Cell Biol. 82 (2): 263–74. doi:10.1139/o03-077. PMID 15060621.
- Tolstrup M, Ostergaard L, Laursen AL; et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. PMID 15078178.
- Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. PMID 15638726.
- Roskoski R (2005). "Src kinase regulation by phosphorylation and dephosphorylation". Biochem. Biophys. Res. Commun. 331 (1): 1–14. doi:10.1016/j.bbrc.2005.03.012. PMID 15845350.
- Alper O, Bowden ET (2005). "Novel insights into c-Src". Curr. Pharm. Des. 11 (9): 1119–30. PMID 15853660.