PDF(Pubmed)
Abstract：
PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is a tumor suppressor that directly dephosphorylates a wide array of substrates, most notably the prosurvival kinase Akt. However, little is known about the molecular mechanisms governing PHLPP1 itself. Here, we report that PHLPP1 is dynamically regulated in a cell cycle-dependent manner and deletion of PHLPP1 results in mitotic delays and increased rates of chromosomal segregation errors. We show that PHLPP1 is hyperphosphorylated during mitosis by Cdk1 in a functionally uncharacterized region known as the PHLPP1 N-terminal extension (NTE). A proximity-dependent biotin identification (BioID) interaction screen revealed that during mitosis, PHLPP1 dissociates from plasma membrane scaffolds, such as Scribble, by a mechanism that depends on its NTE and gains proximity to kinetochore and mitotic spindle proteins such as KNL1 and TPX2. Our data are consistent with a model in which phosphorylation of PHLPP1 during mitosis regulates binding to its mitotic partners and allows accurate progression through mitosis. The finding that PHLPP1 binds mitotic proteins in a cell cycle- and phosphorylation-dependent manner may have relevance to its tumor-suppressive function.
摘要：
PH结构域富含亮氨酸的重复蛋白磷酸酶1（PHLPP1）是一种肿瘤抑制剂，可直接去磷酸化多种底物，最值得注意的是促生存激酶Akt。然而,对控制PHLPP1本身的分子机制知之甚少。这里,我们报道,PHLPP1以细胞周期依赖的方式动态调节,PHLPP1的缺失导致有丝分裂延迟和染色体分离错误的发生率增加.我们表明，在有丝分裂期间，PHLPP1在功能上未表征的区域（称为PHLPP1N末端延伸（NTE））中被Cdk1过度磷酸化。邻近依赖的生物素鉴定(BioID)相互作用筛选显示，在有丝分裂期间，PHLPP1从质膜支架上解离，比如Scribble,通过依赖于其NTE的机制，并获得与动粒和有丝分裂纺锤体蛋白如KNL1和TPX2的接近度。我们的数据与有丝分裂期间PHLPP1的磷酸化调节与其有丝分裂伴侣的结合并允许通过有丝分裂的准确进展的模型一致。PHLPP1以细胞周期和磷酸化依赖性方式结合有丝分裂蛋白的发现可能与其肿瘤抑制功能有关。
