Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane
Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane
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DOI：
10.1073/pnas.0510570103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Devreotes, PN
中科院分区：
文献类型：
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作者：
Vazquez, F;Matsuoka, S;Devreotes, PN
PTEN的肿瘤抑制功能与其使磷脂酰肌醇-3，4，5三磷酸去磷酸化的能力密切相关，从而控制细胞生长、存活和迁移。然而，PTEN在活细胞中的作用机制在很大程度上未被探索。在这里，我们在活细胞中使用单分子TIRF显微镜来揭示酶与膜结合几百毫秒，足以降解几个磷脂酰肌醇-3，4，5三磷酸分子。N-末端脂质结合基序的缺失完全消除了膜相互作用和体内功能。几种机制，包括C-末端尾部磷酸化，似乎保持PTEN在一个约束的构象，限制其与膜的关联率。结合的PTEN的稳态水平在收缩膜的位点处最高，包括高度极化的细胞的后部。动态膜结合可以在时间或空间上进行调节，以改变特定生理情况下的PTEN活性，并且可能对肿瘤抑制功能具有重要影响。
The tumor suppressor function of PTEN is strongly linked to its ability to dephosphorylate phosphatidylinositol-3,4,5 trisphosphate and, thereby, control cell growth, survival, and migration. However, the mechanism of action of PTEN in living cells is largely unexplored. Here we use single-molecule TIRF microscopy in living cells to reveal that the enzyme binds to the membrane for a few hundred milliseconds, sufficient to degrade several phosphaticlylinositol-3,4,5 trisphosphate molecules. Deletion of an N-terminal lipid-binding motif completely abrogates membrane interaction and in vivo function. Several mechanisms, including C-terminal tail phosphorylations, appear to hold PTEN in a constrained conformation that limits its rate of association with the membrane. The steady-state level of bound PTEN is highest at sites of retracting membrane, including the rear of highly polarized cells. The dynamic membrane association could be modulated temporally or spatially to alter PTEN activity in specific physiological situations and could have important implications for tumor suppressor function.