Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.
Deregulated PP1α phosphatase activity towards MAPK activation is antagonized by a tumor suppressive failsafe mechanism.
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DOI：
10.1038/s41467-017-02272-y
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发表时间：
2018-01-15
影响因子：
16.6
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Chen M;Wan L;Zhang J;Zhang J;Mendez L;Clohessy JG;Berry K;Victor J;Yin Q;Zhu Y;Wei W;Pandolfi PP
丝裂原活化蛋白激酶（MAPK）通路在晚期癌症（包括转移性前列腺癌（CaP））中经常异常激活。然而，活化突变或基因重排之间的MAPK信号传导组件，如Ras和Raf，并不总是观察到在癌症与过度活化的MAPK。这些癌症中MAPK激活的潜在机制在很大程度上仍然难以捉摸。在这里，我们发现PPP 1CA基因的基因组扩增在转移性人CaP中高度富集。我们进一步鉴定了导致MAPK信号激活的S6 K/PP 1 α/B-Raf信号通路，该信号通路被PML肿瘤抑制因子拮抗。机制上，我们发现PP 1 α作为B-Raf活化磷酸酶发挥作用，PML通过将PP 1 α隔离到PML核体中抑制MAPK活化，从而抑制S6 K依赖的PP 1 α磷酸化、14-3-3结合和细胞质积累。因此，我们的研究结果揭示了PP 1 α/PML分子网络在人类癌症中发生遗传改变，导致异常MAPK活化，具有重要的治疗意义。MAPK通路的改变在癌症中很常见，但在患者中很少发现突变。在这里，作者发现了PPP 1CA基因在晚期和转移性前列腺癌中的基因组扩增，并确定了这种磷酸酶在ERK信号传导的正调控中的作用。
The mitogen-activated protein kinase (MAPK) pathway is frequently aberrantly activated in advanced cancers, including metastatic prostate cancer (CaP). However, activating mutations or gene rearrangements among MAPK signaling components, such as Ras and Raf, are not always observed in cancers with hyperactivated MAPK. The mechanisms underlying MAPK activation in these cancers remain largely elusive. Here we discover that genomic amplification of the PPP1CA gene is highly enriched in metastatic human CaP. We further identify an S6K/PP1α/B-Raf signaling pathway leading to activation of MAPK signaling that is antagonized by the PML tumor suppressor. Mechanistically, we find that PP1α acts as a B-Raf activating phosphatase and that PML suppresses MAPK activation by sequestering PP1α into PML nuclear bodies, hence repressing S6K-dependent PP1α phosphorylation, 14-3-3 binding and cytoplasmic accumulation. Our findings therefore reveal a PP1α/PML molecular network that is genetically altered in human cancer towards aberrant MAPK activation, with important therapeutic implications. Alterations in the MAPK pathway are common in cancers, yet mutations are rarely found in patients. Here the authors find genomic amplifications of the PPP1CA gene in advanced and metastatic prostate cancer and identify a role for this phosphatase in the positive regulation of ERK signalling.
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