Click on the picture for structural details.
Src, a non-receptor tyrosine kinase, is the product of the first proto-oncogene to be characterized. It plays the role of a protein switch which is turned on by a number of receptor-mediated signals to which it responds by changes in kinase activity and by changes in intracellular localization. In the on state, it phosphorylates proteins with a kinase catalytic domain. Its activity is regulated by multiple regulatory interactions mediated by other parts of its polypeptide chain. There are now nine members in the Src family: Fyn, Yes, Fgr, Lyn, Hck, Lck, Blk and Yrk, in addition to Src itself. Src has a widespread cellular distribution and every eucaryotic cell type studied to date has one or more of its homologs.
Domain Organization: The Src family proteins have the following N to C terminus domain organization, with each domain named as a Src-homology (SH) region.
The Regulatory Switch: Src is autoregulated by intramolecular interactions that lock the molecule in a closed and inactive conformation. Its SH3 domain binds proline residues in the SH2-kinase linker, and its SH2 domain binds a pY (tyrosine 527 phosphorylated by Csk kinase) making the kinase catalytic domain inaccessible to other proteins. V-Src, the oncogene product from the Rous Sarcoma Virus, an avian retrovirus, is a constitutively active kinase with a deleted carboxyl terminus. Mutations in either the SH2 or the SH3 domain also can affect the stability of the closed, inactive conformation leading to activation.
Src changes its conformation to an open and active state by dephosphorylation of Y527 or by apposition of a high-affinity ligand for the SH2 or the SH3 domains, which disrupt the intramolecular interactions that maintain the closed state.
>August 15, 1997