P60c-src

Definition

The cellular proto-oncogene p60c-src (src) is a cytosolic nonreceptor tyrosine kinase.

Discovery

In 1911, Peyton Rous reported that a fibrosarcoma could be transmitted between chickens in a cell-free extract of the tumor1. The transmissible agent, Rous sarcoma virus (RSV), transforms cells by virtue of the presence within its genome of a viral oncogene, v-src, which is derived from a normal cellular gene that has been picked up, or transduced, by the virus. This cellular proto-oncogene, c-src, encodes a protein, p60c-src, which has the ability to phosphorylate proteins on tyrosine residues. Studies of RSV were thus directly responsible for the discovery of cellular proto-oncogenes and of protein-tyrosine kinases, discoveries which have been fundamental in shaping ideas about cellular growth control2.

Structural Characteristics

The c-src gene family has nine known members (blk, c-fgr, fyn, hck, lck, lyn, c-src, c-yes and yrk), each encoding a cytoplasmic protein-tyrosine kinase (PTK) believed to be involved in signal transduction. The c-src PTKs contain three domains (SH1, SH2 and SH3) that are found in many other signalling proteins. The SH1 domain has PTK activity, whilst the SH2 and SH3 domains are involved in mediating protein-protein interactions by binding to phosphotyrosine-containing and proline-rich motifs, respectively3.

Mode of Action

A study showed that, when compared to the DNA sequence of the parental c-src viruses, the two transforming mutant src viruses contain single point mutations that result in single amino acid changes in the src gene products (p60 proteins). Both amino acid changes reside in the tyrosine kinase domain of the protein. The mutation detected in one virus involves replacement of the normal Glu-378 in p60c-src by Gly, whereas the p60 of the other transforming virus has Phe instead of the normal Ile-441. This indicates that when p60c-src is expressed at elevated levels in a retroviral context, a single amino acid change in its primary sequence can activate the kinase activity of this protein and cause cellular transformation4.

Functions

p60c-src function in a broad range of biological situations, regulating the behaviour of terminally differentiated, post-mitotic cell types. Targeted disruption of members of the c-src family in transgenic mice has confirmed important roles in T-lymphocyte maturation and activation. p60c-src also plays an important role in bone maintenance, learning, memory and signal transduction which mediate cell growth, differentiation, transformation and tissue remodeling in various organs5.

References:
1.Rous P (1911). A Sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med., 13 (4):397-411.
2.Brickell PM (1992). The p60c-src family of protein-tyrosine kinases: structure, regulation, and function. Crit. Rev. Oncog.,
3(4):401-446. 3.Kefalas P, Brown TR, Brickell PM (1995). Signalling by the p60c-src Family of Protein-Tyrosine Kinases. Int J Biochem Cell Biol., 27(6):551-563.
4.Levy JB, Iba H, Hanafusa H (1986). Activation of the transforming potential of p60c-src by a single amino acid change. PNAS., 83(12):4228-4232.
5.Kefalas P, Brown TR, Brickell PM (1995). Signalling by the p60c-src family of protein-tyrosine kinases. Int J Biochem Cell Biol., 27(6):551-563.

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