The Role of Src in Solid Tumors

Abstract

The proto-oncogene c-Src (Src) is a nonreceptor tyrosine kinase whose expression and activity is correlated with advanced malignancy and poor prognosis in a variety of human cancers. Nine additional enzymes with homology to Src have been identified and collectively are referred to as the Src family kinases (SFKs). Together, SFKs represent the largest family of nonreceptor tyrosine kinases and interact directly with receptor tyrosine kinases, G-protein-coupled receptors, steroid receptors, signal transducers and activators of transcription and molecules involved in cell adhesion and migration. These interactions lead to a diverse array of biological functions including proliferation, cell growth, differentiation, cell shape, motility, migration, angiogenesis, and survival. Studies investigating mutational activation of Src in human cancers suggest this may be a rare event and wild-type Src is weakly oncogenic. Thus, the role of Src in the development and progression of human cancer has remained unclear. Recently, it has been suggested that increased SFK protein levels and, more importantly, SFK tyrosine kinase activity is linked to cancer progression and metastatic disease by facilitating the action of other signaling proteins. This accumulating body of evidence indicates that SFKs may represent a promising therapeutic target for the treatment of solid tumors. This review discusses the role of SFKs in solid tumors and the recent therapeutic advances aimed at targeting this family of tyrosine kinases in cancer.

Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1

“…Insufficient Src activation paralyzes the cell and prevents the turnover of focal adhesions (Fincham and Frame, 1998), whereas excessive Src activation can promote the spreading of cancer cells, invasion and metastasis (Wheeler et al, 2009). Accordingly, exquisite regulation of Src activity is paramount to normal cell behavior.…”

“…These processes are also intricately involved in pathological conditions such as wound healing, atherosclerosis and cancer (Friedl and Gilmour, 2009). The non-receptor tyrosine kinase Src, the founding member of the Src family kinases (SFKs), plays key roles in regulating cell adhesion and migration (Fincham and Frame, 1998), and the deregulation of Src kinase activity in cancer is correlated with metastasis and poor survival (Wheeler et al, 2009). Each SFK is characterized by a prototypical structure defined by: an N-terminal SH4 lipid-modification domain (Koegl et al, 1994), an unique domain, a type-II proline-rich-binding SH3 domain, a phospho-tyrosine-binding SH2 domain (Payne et al, 1993), a proline-rich linker region, an SH1 kinase domain containing a crucial autophosphorylation site (Smart et al, 1981), and a C-terminal regulatory domain (Cooper et al, 1986) containing a crucial tyrosine residue (Y529 in human Src) that is phosphorylated by C-terminal Src kinase (CSK) (Nada et al, 1991).…”

Targeting Cas Family Proteins as a Novel Treatment for Breast Cancer

“…In addition to phosphorylating the p130 Cas SD, cSrc binds to phosphorylated tyrosine residues within SD in vitro (Shin et al 2004). SFKs have a conserved structure containing SH1 (kinase), SH2, SH3, and SH4 (membrane targeting) domains and transactivate interacting partners by phosphorylation resulting in the activation of multiple signaling pathways as presented in part in Figure 1 (reviewed in Mayer & Krop 2010;Wheeler et al 2009). The kinase activity is tightly regulated by tyrosinephosphorylation on the carboxyl terminus by CSK (c-src tyrosine kinase) resulting in intramolecular binding and an inactive closed conformation (Superti-Furga et al 1993).…”

Ammonium Vanadate Decreases Viability and Proliferation Activity of Cultured Virustransformed Rat Sarcoma Cells

“…Src can regulate a number of signalling pathways that have impact on the behaviour of tumour cells, including proliferation, differentiation, survival, migration, invasion and angiogenesis. Abnormal expression of these genes has been documented in cancers that arise in the breast, colon, ovary, melanocyte, gastric mucosa, head and neck, pancreas, lung, and brain [15][16][17].…”