PI(3,4)P2-mediated membrane tubulation promotes integrin trafficking and invasive cell migration
Menée à l'aide de cellules fibroblastiques et de lignées cellulaires de cancer du sein, cette étude met en évidence un mécanisme par lequel la tubulation de la membrane cellulaire induite par les phospholipides PI(3,4)P2 favorise le trafic des intégrines et la migration invasive des cellules
Résumé en anglais
The dynamic distribution of phosphoinositide lipids orchestrates intracellular compartmentalization and protein sorting. Here, we report the PI(3,4)P2-dependent endocytosis of adhesion receptor integrin-beta3 at the invadopodium and its implication in promoting invasive cell migration. PI(3,4)P2-rich compartment in the plasma membrane contains integrin-beta3 and is actively internalized through SNX9-mediated membrane invagination as well as dynein-mediated membrane tubulation along cortical microtubule tracks. Accelerated integrin endocytosis promotes adhesion turnover, and subsequent integrin exocytosis further supports cell migration. In general, the functional link between PI(3,4)P2 biogenesis and membrane internalization can be applicable to other membrane molecules at the invadopodium and provide insights into the regulation of cell migration.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.All study data are included in the article and/or supporting information.
