Src (gene)

Src is a family of proto-oncogenic tyrosine kinases originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the Nobel Prize. [ [http://nobelprize.org/nobel_prizes/medicine/laureates/1989/press.html Nobel Prize in Physiology or Medicine for 1989 jointly to J. Michael Bishop and Harold E. Varmus for their discovery of "the cellular origin of retroviral oncogenes".] Press Release.] 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.

PBB_Summary
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summary_text = This gene is 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. [cite web | title = Entrez Gene: SRC v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6714| accessdate = ]

v-src

Francis Peyton Rous first proposed that viruses can cause cancer. He proved it in 1911. Chickens grow a tumor called a fibrosarcoma. Rous ground up these sarcomas, centrifuged them to remove the solid material, and injected the remaining liquid into chicks. The chicks developed sarcomas. The causative agent in the liquid was a virus, now called Rous sarcoma virus (RSV).

Later work by others showed that RSV was a type of retrovirus. Non-cancer-forming retroviruses contain three 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.cite journal |author=Stehelin D, Fujita DJ, Padgett T, Varmus HE, Bishop JM. |title=Detection and enumeration of transformation-defective strains of avian sarcoma virus with molecular hybridization |journal= Virology |volume=76 |issue=2 |pages=675–84 |year=1977 |pmid=190771 |doi=10.1016/0042-6822(77)90250-1]

A function for Src tyrosine kinases in normal cell growth was first demonstrated with the binding of family member p56lck to the cytoplasmic tail of the CD4 and CD8 co-receptors on T-cells.cite journal | author = Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF | title = The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 14 | pages = 5190–4 | year = 1988 | month = July | pmid = 2455897 | pmc = 281714 | doi = | url = http://www.pnas.org/content/85/14/5190.abstract | issn = ] Src tyrosine kinases also 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".cite journal |author=Tal J, Fujita DJ, Kawai S, Varmus HE, Bishop JM |title=Purification of DNA complementary to the env gene of avian sarcoma virus and analysis of relationships among the env genes of avian leukosis-sarcoma viruses |journal= J Virol. |volume=21 |issue=2 |pages=497–505 |year=1977 |pmid=189084] The normal cellular gene was called "c-src" (cellular-src).cite journal |author=Oppermann H, Levinson AD, Varmus HE, Levintow L, Bishop JM |title=Uninfected vertebrate cells contain a protein that is closely related to the product of the avian sarcoma virus transforming gene (src) |journal=Proc Natl Acad Sci U S A. |volume=76 |issue=4 |pages=1804–8 |year=1979 |pmid=221907 |doi=10.1073/pnas.76.4.1804] 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 number|2.7.10.2), that associates with the cytoplasmic face of the plasma membrane. The protein consists of three 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.

rc family kinases

The Src family includes nine mammalian members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates.

ee also

* C-src tyrosine kinase

External links

* [http://vega.sanger.ac.uk/Homo_sapiens/geneview?db=core;gene=OTTHUMG00000032417 Vega geneview]
*MeshName|src-Family+Kinases
*MeshName|src+Gene

References

*Lodish, Harvey; Burk, Arnold; Zipurksy, Lawrence, et al. "Cancer" in "Molecular Cell Biology". 4th edition. 2000. ISBN 0-7167-3706-X. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=mcb.section.7090]

Further reading

PBB_Further_reading
citations =
*cite journal | author=Frame MC, Fincham VJ, Carragher NO, Wyke JA |title=v-Src's hold over actin and cell adhesions |journal=Nat. Rev. Mol. Cell Biol. |volume=3 |issue= 4 |pages= 233–45 |year= 2002 |pmid= 11994743 |doi= 10.1038/nrm779
*cite journal | author=Benaim G, Villalobo A |title=Phosphorylation of calmodulin. Functional implications |journal=Eur. J. Biochem. |volume=269 |issue= 15 |pages= 3619–31 |year= 2002 |pmid= 12153558 |doi=10.1046/j.1432-1033.2002.03038.x
*cite journal | author=Simeonova PP, Luster MI |title=Arsenic carcinogenicity: relevance of c-Src activation |journal=Mol. Cell. Biochem. |volume=234-235 |issue= 1-2 |pages= 277–82 |year= 2003 |pmid= 12162444 |doi=10.1023/A:1015971118012
*cite journal | author=Leu TH, Maa MC |title=Functional implication of the interaction between EGF receptor and c-Src |journal=Front. Biosci. |volume=8 |issue= |pages= s28–38 |year= 2004 |pmid= 12456372 |doi=10.2741/980
*cite journal | author=Greenway AL, Holloway G, McPhee DA, "et al." |title=HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication |journal=J. Biosci. |volume=28 |issue= 3 |pages= 323–35 |year= 2004 |pmid= 12734410 |doi=
*cite journal | author=Dehm SM, Bonham K |title=SRC gene expression in human cancer: the role of transcriptional activation |journal=Biochem. Cell Biol. |volume=82 |issue= 2 |pages= 263–74 |year= 2004 |pmid= 15060621 |doi= 10.1139/o03-077
*cite journal | author=Tolstrup M, Ostergaard L, Laursen AL, "et al." |title=HIV/SIV escape from immune surveillance: focus on Nef |journal=Curr. HIV Res. |volume=2 |issue= 2 |pages= 141–51 |year= 2004 |pmid= 15078178 |doi=10.2174/1570162043484924
*cite journal | author=Joseph AM, Kumar M, Mitra D |title=Nef: "necessary and enforcing factor" in HIV infection |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 87–94 |year= 2005 |pmid= 15638726 |doi=10.2174/1570162052773013
*cite journal | author=Roskoski R |title=Src kinase regulation by phosphorylation and dephosphorylation |journal=Biochem. Biophys. Res. Commun. |volume=331 |issue= 1 |pages= 1–14 |year= 2005 |pmid= 15845350 |doi= 10.1016/j.bbrc.2005.03.012
*cite journal | author=Alper O, Bowden ET |title=Novel insights into c-Src |journal=Curr. Pharm. Des. |volume=11 |issue= 9 |pages= 1119–30 |year= 2005 |pmid= 15853660 |doi=10.2174/1381612053507576

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