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PI(3,4)P2-mediated membrane tubulation promotes integrin trafficking and invasive cell migration [Cell Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-05-11 , DOI: 10.1073/pnas.2017645118
Zhen Feng 1 , Cheng-Han Yu 2
Affiliation  

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.



中文翻译:

PI(3,4)P2 介导的膜管化促进整合素运输和侵袭性细胞迁移 [细胞生物学]

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。

更新日期:2021-05-05
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