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.

Invadopodia 是整合素介导的粘连，具有丰富的 PI(3,4)P ₂。然而，PI(3,4)P ₂在粘附信号传导中的功能作用仍不清楚。在这里，我们发现 PI(3,4)P ₂生物发生调节 invadopodia 的整合素内吞作用。PI(3,4)P ₂由 PIK3CA 和 SHIP2 局部产生，并集中在侵入足弧的后缘。PI(3,4)P ₂丰富的隔室以 SNX9 依赖性方式局部形成小点（膜芽），通过 AKTIP 招募动力蛋白激活剂 Hook1，并重新排列成微米长的管状内陷（膜管）。未弯曲的膜管迅速延伸，跟随动力蛋白沿微管轨迹的逆行运动，并与质膜断开。激活的整合素-β3 通过 PI(3,4)P ₂介导的膜内陷途径局部内化，然后被积极回收。PI3K、SHIP2 和 SNX9 的阻断抑制整合素-β3 内吞作用，延迟粘附周转，并阻碍 MEF-Src 和 MDA-MB-231 细胞的 transwell 侵袭。因此，PI(3,4)P _{2 的产生} 通过刺激 invadopodium 上整合素受体的运输促进侵入性细胞迁移。