ABSTRACT
Many excellent reviews have been published describing in great detail the history of the discovery of the Src family kinases (SFKs), their molecular structure, their, biochemical properties, and their functions in normal tissues. In addition, many papers have described the effects of exogenous expression of viral or mutated forms of c-Src (v-Src) that may or may not represent the biology of deregulated c-Src found in cancer cells. In this review, emphasis is given to evidence found in cancer tissue or cell lines derived from tumors. In addition, small molecule inhibitors targeting Src family kinases are reviewed, from the first broad-spectrum compounds described in the early 1990s to the present day drugs used in the clinic.
Src FAMILY KINASES AS TARGETS Link Between Src Family Kinases and Cancer c-Src was the first protein kinase to be identified as selective for tyrosine residues. Its tyrosine kinase activity was initially discovered by studying the 60 kDa protein encoded by the v-Src gene in the chicken Rous sarcoma virus (1,2). The presence of a similar protein in vertebrate cells had already been described (3) and the cellular chicken gene was soon characterized (4). Together, these discoveries led to the awarding of the 1989 Nobel Prize in Physiology and Medicine to Harold Varmus and Michael Bishop. According to the official nomenclature for viral and cellular counterparts, the viral form is known as v-Src and the cellular gene as c-Src (5). The domain structure of c-Src is very highly conserved across species and throughout all the 8 SFKs (c-Src, c-Yes, Fyn, Lyn, Fgr, Lck, Hck, Blk) known today in humans. The C-terminal half is a consensus tyrosine kinase domain containing an autophosphorylation site at Tyr419 (Tyr416 in the chicken sequence). The N-terminal half is more divergent and contains a membrane docking sequence that is myristoylated in all SFKs and additionally palmitoylated in all SFKs except c-Src and Blk (6,7), followed by an SH3 domain and an SH2 domain. In all SFKs, the SH2 domain interacts with a phosphorylated tyrosine at position 530 in the C-terminal end (human c-Src nomenclature). The SH2-P-Tyr530 interaction maintains the kinase in a closed conformation preventing autophosphorylation and substrate phosphorylation (8-10). The kinase responsible for this phosphorylation is called Csk (C-terminal Src kinase) (11). Contrary to c-Src, Csk is a cytoplasmic protein that is recruited to the membrane by docking proteins in order to phosphorylate c-Src. Since c-Src is found to be overactivated in tumors, it is likely that Csk is unable to downregulate c-Src activity in cancer cells. Surprisingly, Csk levels were found to be up to 10 times higher in tumors compared with healthy tissue (12). Whether Csk is inactive or simply uncoupled from c-Src inhibition is unclear.
