Vav2 shows muscle: new roles for this Rho-GEF in skeletal muscle and the development of metabolic syndrome.
Speaker: Sonia Rodríguez Fernández
Centro de Investigación del Cáncer (CIC-IBMCC), laboratorio 2
Salón de Actos del Centro de Investigación del Cáncer
Rho guanosine nucleotide exchange factors are enzymes that play key roles in the control of the stereospatial activation of Rho GTPases during both physiological and pathological conditions. Despite this, there is still little information regarding the roles played by them at the organismal level and the magnitude of the contribution of their catalysis-mediated pathways to those processes.
To tackle those issues in the case of the Vav2 GEF, we have generated two complementary genetically engineered mouse strains, one expressing a hypomorphic form of Vav2 with very low catalytic activity and the other expressing a version with constitutive exchange activity.
Using these models, we have discovered the implication of Vav2 catalysis-dependent functions in the response of skeletal muscle cells to insulin and IGF via a PI3K dependent mechanism and how these defects determine the development of a post-insulin receptor diabetes-like condition in mice carrying the “pharmaco-mimetic” or catalytically deficient version of Vav2. Conversely, the expression of the hyperactive version of Vav2 protects against the development of metabolic syndrome, type II diabetes, and associated comorbidities that typically develop during both aging and under the administration of high fat diets.
Furthermore, our latest results demonstrate that Vav2 catalytic activity plays also a role in the latest steps of myoblasts differentiation.
These results unveil a hitherto unknown GEF-dependent pathway that operates in skeletal muscle cells and, in addition, indicate that the chronic administration of inhibitors to the catalytic domain of Vav2 can lead to the long-term development of a metabolic condition in patients.