Pleiotropic roles of Vav family oncoproteins in skin and oral tumorigenesis

MAURICIO ARIEL MENACHO; XOSÉ R. BUSTELO

Barcelona

Congreso; XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular; 2011

SEBBM

The Vav family is a group of oncogenic signal transduction molecules that work as activators of Rho/Rac GTPases. In mammals, this family has three members: Vav1, Vav2, and Vav3. Recent work has shown that these proteins play roles in a number of physiological processes, including immune responses and cardiovascular homeostasis. The use of gain- of-function mutants also demonstrated that they can promote tumorigenesis in cell culture. However, no evidence is yet available regarding the actual implication of Vav proteins on tumor development in vivo. To address this issue, we have used single and compound Vav family knockout animals in models of skin and oral tumorigenesis. Here, we will report that the endogenous Vav2 and Vav3 are important for the evolution of these two tumor types. We will also demonstrate that Vav proteins control signaling events critical for intrinsic keratinocyte survival and mitogenic pathways as well as for the engagement of extrinsic processes such as inflammation and angiogenesis. Interestingly, we have discovered that most Vav family- dependent biological processes are associated with the induction of paracrine loops involving mitogenic factors and cytokines. Finally, we will also show that the Vav family gene deficiency does not affect the homeostasis of normal epithelia, thus suggesting that anti-Vav family therapies will affect specifically tumors and not normal cells. Taken together, these data indicate that Vav proteins may represent good therapeutic targets for these tumor types.