Cell growth and metastasis in pancreatic cancer: is Vav the Rho'd to activation?

The best-known family of low molecular weight GTP-binding proteins is Ras, owing to their high incidence of gain of function mutations in a variety of human cancers including pancreatic cancer. Unlike Ras, no activating mutations have been observed thus far for Rho family GTP-binding proteins in cancer, yet there is increasing evidence that overexpression of Rho family members and/or dysregulation of the GDP-->GTP cycle play an important role in cancer development and progression. The activation of Rho family GTPases downstream of cell surface receptors results in the induction of several intracellular signaling cascades that have been shown to impact on such diverse cellular responses as reorganization of the actin cytoskeleton, gene transcription, cell survival, and cell proliferation. One family of guanine nucleotide exchange factors (GEFs) that have the potential to couple the activation of Rho family members to upstream growth factor receptor tyrosine kinases (RTKs) is the Vav family of proto-oncogenes. Recent experimental evidence has implicated Vav in the regulation of numerous Rho-mediated pathways downstream of RTKs and other cell surface receptors. In this review, we will discuss our current understanding of how Vav proteins are regulated, and how Vav and their target GTP-binding proteins participate in tumorigenesis.