PIP3 abundance overcomes PI3K signaling selectivity in invadopodia.

ABSTRACT

PI3Kß is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kß and its coupling to SHIP2 to produce PI(3,4)P2 . We now test whether selectivity for PI3Kß is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kß is inhibited, short-chain diC8-PIP3 rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2 is SHIP2-independent. Surprisingly, the expression of either activated PI3Kß or PI3Kα mutants rescued the effects of PI3Kß inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.