PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells
PR55α regulatory subunit of PP2A inhibits the MOB1/LATS cascade and activates YAP in pancreatic cancer cells
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DOI：
10.1038/s41389-019-0172-9
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发表时间：
2019-10-28
期刊：
影响因子：
6.2
通讯作者：
Yan, Ying
中科院分区：
文献类型：
--
作者：
Hein, Ashley L.;Brandquist, Nichole D.;Yan, Ying
PP 2A全酶复合物负责人细胞中大部分Ser/Thr磷酸酶活性。每个PP 2A由催化亚基（C）、支架亚基（A）和调节亚基（B）组成。虽然A和C亚基各自仅存在于两种高度保守的同种型中，但大量的B亚基没有同源性，这决定了PP 2A底物特异性和细胞定位。预计不同的PP 2A全酶在细胞信号网络中发挥不同的作用，而PP 2A通常仅被定义为推定的肿瘤抑制剂，这主要是基于使用PP 2A的高度保守的A或C亚基的药理学或生物学抑制剂的功能丧失研究。最近的研究表明，特定的途径，一些PP 2A复合物也具有促肿瘤功能。我们以前曾报道过PR 55 α（PP 2A调节亚基）在支持致癌表型（包括胰腺癌细胞的体内致瘤性/转移）中的重要作用。在这份报告中，我们已经阐明了一个新的作用PR 55 α调节PP 2A在激活雅普癌蛋白，其功能是所需的锚定独立生长在实体瘤的肿瘤发生。我们的数据显示了PR 55 α对雅普的两条调控线：（1）PR 55 α抑制MOB 1触发的LATS 1/2激酶的自激活，LATS 1/2激酶是Hippo通路的核心成员，通过诱导其蛋白酶体降解和细胞质滞留来抑制雅普，（2）PR 55 α直接与雅普本身相互作用并对其进行调控。因此，PR 55 α对于YAP促进的基因转录以及锚定非依赖性生长是必需的，其中雅普起关键作用。总之，目前的研究结果表明，一种新的雅普激活机制的基础上PR 55 α调节PP 2A磷酸酶。
PP2A holoenzyme complexes are responsible for the majority of Ser/Thr phosphatase activities in human cells. Each PP2A consists of a catalytic subunit (C), a scaffold subunit (A), and a regulatory subunit (B). While the A and C subunits each exists only in two highly conserved isoforms, a large number of B subunits share no homology, which determines PP2A substrate specificity and cellular localization. It is anticipated that different PP2A holoenzymes play distinct roles in cellular signaling networks, whereas PP2A has only generally been defined as a putative tumor suppressor, which is mostly based on the loss-of-function studies using pharmacological or biological inhibitors for the highly conserved A or C subunit of PP2A. Recent studies of specific pathways indicate that some PP2A complexes also possess tumor-promoting functions. We have previously reported an essential role of PR55 alpha, a PP2A regulatory subunit, in the support of oncogenic phenotypes, including in vivo tumorigenicity/metastasis of pancreatic cancer cells. In this report, we have elucidated a novel role of PR55 alpha-regulated PP2A in the activation of YAP oncoprotein, whose function is required for anchorage-independent growth during oncogenesis of solid tumors. Our data show two lines of YAP regulation by PR55 alpha: (1) PR55 alpha inhibits the MOB1-triggered autoactivation of LATS1/2 kinases, the core member of the Hippo pathway that inhibits YAP by inducing its proteasomal degradation and cytoplasmic retention and (2) PR55 alpha directly interacts with and regulates YAP itself. Accordingly, PR55 alpha is essential for YAP-promoted gene transcriptions, as well as for anchorage-independent growth, in which YAP plays a key role. In summary, current findings demonstrate a novel YAP activation mechanism based on the PR55 alpha-regulated PP2A phosphatase.