Mst1 Is an Interacting Protein that Mediates PHLPPs' Induced Apoptosis
Mst1 Is an Interacting Protein that Mediates PHLPPs' Induced Apoptosis
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DOI：
10.1016/j.molcel.2010.03.017
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发表时间：
2010-05-28
期刊：
影响因子：
16
通讯作者：
Pardee, Arthur B.
中科院分区：
文献类型：
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作者：
Qiao, Meng;Wang, Yaqi;Pardee, Arthur B.
PHLPP1和PHLPP2磷酸酶通过在几种乳腺癌和胶质母细胞瘤细胞中Akt的去磷酸化和失活发挥其肿瘤抑制功能。然而，Akt或其他已知的PHLPPs靶点（包括PKC和ERK）可能无法完全阐明多功能磷酸酶的生理作用，尤其是其强大的凋亡诱导功能。在这里，我们表明，PHLPPs诱导癌细胞凋亡的独立的PHLPPs的已知目标。我们确定Mst 1作为一个结合伙伴，在体内和体外与PHLPPs相互作用。PHLPPs使Mst 1在1387抑制位点去磷酸化，从而激活Mst 1及其下游效应子p38和JNK以诱导凋亡。同样的1387位点可以被Akt磷酸化。因此，PHLPP，Akt和Mst 1构成了一个自抑制三角形，控制细胞类型和环境依赖性的细胞凋亡和增殖的精细平衡。
PHLPP1 and PHLPP2 phosphatases exert their tumor-suppressing functions by dephosphorylation and inactivation of Akt in several breast cancer and glioblastoma cells. However, Akt, or other known targets of PHLPPs that include PKC and ERK, may not fully elucidate the physiological role of the multifunctional phosphatases, especially their powerful apoptosis induction function. Here, we show that PHLPPs induce apoptosis in cancer cells independent of the known targets of PHLPPs. We identified Mst1 as a binding partner that interacts with PHLPPs both in vivo and in vitro. PHLPPs dephosphorylate Mst1 on the 1387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis. The same 1387 site can be phosphorylated by Akt. Thus, PHLPP, Akt, and Mst1 constitute an autoinhibitory triangle that controls the fine balance of apoptosis and proliferation that is cell type and context dependent.