The road to Src

Abstract

More than a quarter of a century has elapsed since the identification of the c-src proto-oncogene. During that period, we have learned that cancer arises as the result of mutations in proto-oncogenes and tumor suppressor genes, and we are now seeing the first fruits of these discoveries, in the form of targeted therapies directed against activated tyrosine kinases such as Bcr-Abl, c-Kit and the EGF receptor. But the discovery of the c-src proto-oncogene was in turn based on decades of study on an avian RNA tumor virus, Rous sarcoma virus (RSV). Here I review the work that led up to the identification of the RSV transforming gene and its protein product, and how this information in turn led to the discovery of cellular Src.

Molecular dynamics and protein function

“…The coupling between the SH2 and SH3 domains is the key to this intersite communication in Src and underlies the importance of the phosphotyrosine-SH2 linkage at the base of the distal surface of the kinase domain. If this linkage is broken, as in the form of the protein produced by the v-Src oncogene, the kinase activity of Src is turned on constitutively (67). The molecular dynamics simulations show that the residues in the SH2 domain that interact with the phosphotyrosine residue in the tail move significantly when the activation loop in the kinase domain is displaced.…”

“…The Src tyrosine kinases are a family of closely related proteins that transmit signals initiated by growth factor receptors in human cells (67). A mutant and constitutively activated form of Src is encoded by the first oncogene to be discovered (v-Src; so named for the sarcomas caused by the expression of this retroviral gene).…”

Identification of avian leukosis virus subgroup J-associated acutely transforming viruses carrying the v-src oncogene in layer chickens

“…The main differences found among the SJ-1-SJ-5 genomes were the insertion site and the length of the v-src oncogene. The v-src oncogenes in SJ-1 and SJ-2 encoded a p60 v-src protein with a deletion mutation of Tyr527 and downstream amino acids compared with p60 c-src , which appeared to be crucial for transforming activity, as described previously (Martin, 2001(Martin, , 2004Wyke, 1983). Sequence analysis also revealed that the SJ-3, SJ-4 and SJ-5 viral genomes did not directly express the Src oncoprotein.…”

Src Points the Way to Biomarkers and Chemotherapeutic Targets

“…[6][7][8] Huebner and Todaro proposed that all animal cells contain viral "oncogenes" that are transmitted to progeny cells in a repressed form as "proto-oncogenes." 5,9,10 The cellular version of v-Src was confirmed by seminal work carried out by the groups of Varmus, Bishop, Cooper, and Hanafusa. [11][12][13][14] Proto-oncogenes, exemplified by Src, can cause cancer when altered by physical or chemical agents.…”

“…[16][17][18][19] However, unlike v-Src, c-Src has low transforming ability unless it is overexpressed and/or mutated. 10 As with most tumor cells, Srctransformed cells display characteristic phenotypes that include rounded morphology, increased motility, uncontrolled proliferation, anchorage independence, and growth factor independence. Furthermore, Src leads to the disruption of the actin cytoskeleton as well as cell-cell and cell-matrix adhesions.…”