The Role of Src Family Kinases in Prostate Cancer

In 1911 Peyton Rous described a transmissible agent that could induce sarcoma in chicken, this was later identifi ed as a virus and named Rous Sarcoma Virus (Rous, 1911). Identifi cation of the viral tyrosine kinase v-Src and its cellular counterpart c-Src (later in the text referred as Src), introduced the concept of proto-oncogene which has had a signifi cant impact on the progress of our knowledge of carcinogenesis (Martin, 2001). Since its description, Src has been implicated in a variety of malignancies (Frame, 2002) including prostate cancer (Chang et al. 2007), which is the most commonly diagnosed cancer in men and the second leading cause of cancer-related death in men in the U.K. and U.S. (Jemal et al. 2007). The Src-family kinases (SFK) comprises of nine members including Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn; Src, Fyn and Yes being ubiquitously expressed in all cells while other kinases are tissue specifi c. Apart from Src, two other family members, Fgr (Edwards et al. 2003) and Lyn (Goldenberg-Furmanov et al. 2004) have been implicated in prostate cancer. All SFK members share similar structure; each protein consists of four Src homology (SH) domains and a unique amino-terminal domain. High resolution crystallographic analysis of Src revealed the complex nature of structural changes involved in switching between active and inactive state. Src can be locked in an inactive conformation when its negative regulatory tail is phosphorylated at tyrosine Y530 by c-terminal Src kinase (Csk). However, when Src becomes autophosphorylated at tyrosine Y419, which is located in the kinase domain, the protein unfolds assuming its catalytically active conformation. Apart from being a tyrosine kinase, Src may function as a scaffolding molecule being an adaptor for other intracellular proteins that in turn can activate Src by the release of its intramolecular bonds. Another mechanism of Src activation, called peripheral targeting, involves translocation of inactive Src, which is located in the perinuclear region, to the cell periphery where Src becomes attached to the inner surface of cell membrane by its myristoylation fragment (Frame, 2002).Src interacts with a wide variety of proteins including receptor tyrosine kinases, G-protein coupled receptors, steroid receptors, integrins, other non-receptor protein kinases etc., which is re fl ected in the multiplicity of resulting cellular biological events (Thomas and Brugge, 1997). Crosstalk between Src and the components of PI3K (phosphatidylinositol 3-kinase) and MAPK (mitogen activated protein kinase) pathways may affect tumor cell proliferation and apoptosis while involvement in focal adhesion complexes, especially FAK (focal adhesion kinase), paxillin and p130CAS (p130 Crk-associate sub-strate) plays an important part in promoting cell adhesion, migration and invasion (Summy and Gallick, 2006). Considering its unique position at the crossroads of the intracellular signaling networks, Src has become an attractive target in the search of novel prostate cancer therapies (McCarty, 2004).