PI(3,4)P₂-mediated membrane tubulation promotes integrin trafficking and invasive cell migration.

Abstract

Invadopodia are integrin-mediated adhesions with abundant PI(3,4)P₂ However, the functional role of PI(3,4)P₂ in adhesion signaling remains unclear. Here, we find that the PI(3,4)P₂ biogenesis regulates the integrin endocytosis at invadopodia. PI(3,4)P₂ is locally produced by PIK3CA and SHIP2 and is concentrated at the trailing edge of the invadopodium arc. The PI(3,4)P₂-rich compartment locally forms small puncta (membrane buds) in a SNX9-dependent manner, recruits dynein activator Hook1 through AKTIP, and rearranges into micrometer-long tubular invaginations (membrane tubes). The uncurving membrane tube extends rapidly, follows the retrograde movement of dynein along microtubule tracks, and disconnects from the plasma membrane. Activated integrin-beta3 is locally internalized through the pathway of PI(3,4)P₂-mediated membrane invagination and is then actively recycled. Blockages of PI3K, SHIP2, and SNX9 suppress integrin-beta3 endocytosis, delay adhesion turnover, and impede transwell invasion of MEF-Src and MDA-MB-231 cells. Thus, the production of PI(3,4)P₂ promotes invasive cell migration by stimulating the trafficking of integrin receptor at the invadopodium.