Increased Rac activity is required for the progression of T-lymphomas induced by Pten-deficiency.

Abstract

Mutation of the tumor suppressor PTEN results in loss of its PI3-kinase counteracting function. PI3-kinase stimulates tumor formation by PKB/Akt-mediated cell proliferation and prevention of apoptosis. PI3-kinase may also activate Rho-GTPases and their regulatory GEFs to promote invasion. Here we have analyzed the function of the Rac-specific activator, Tiam1, in PI3-kinase-induced T-lymphomagenesis. Mice with a T cell-specific Pten deletion developed T-lymphomas with enhanced PKB/Akt phosphorylation. However, these T-lymphomas infiltrated more frequently into various organs in Tiam1-deficient mice compared to wild type mice. Surprisingly, Tiam1-deficient lymphomas showed increased Rac activity, suggesting that the lack of Tiam1 is compensated by alternative Rac-activating mechanisms that lead to increased progression of PI3-kinase-induced T-lymphomas.