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. 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.
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.
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. 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.
src: The transforming (sarcoma inducing) gene of Rous sarcoma virus. The protein product is pp60vsrc, a cytoplasmic protein with tyrosine-specific protein kinase activity 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.