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 PR55α, 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 PR55α-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 PR55α: (1) PR55α 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) PR55α directly interacts with and regulates YAP itself. Accordingly, PR55α 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 PR55α-regulated PP2A phosphatase.

PP2A 全酶复合物负责人类细胞中的大部分 Ser/Thr 磷酸酶活性。每个 PP2A 由一个催化亚基 （C）、一个支架亚基 （A） 和一个调节亚基 （B） 组成。虽然 A 和 C 亚基分别仅以两种高度保守的亚型存在，但大量 B 亚基没有同源性，这决定了 PP2A 底物特异性和细胞定位。预计不同的 PP2A 全酶在细胞信号网络中起着不同的作用，而 PP2A 通常仅被定义为推定的肿瘤抑制因子，这主要基于使用药理学或生物抑制剂对 PP2A 高度保守的 A 或 C 亚基进行功能丧失研究。最近对特定途径的研究表明，一些 PP2A 复合物也具有促进肿瘤的功能。我们之前已经报道了 PP2A 调节亚基 PR55α 在支持致癌表型中的重要作用，包括胰腺癌细胞的体内致瘤性/转移。在本报告中，我们阐明了 PR55α 调节的 PP2A 在 YAP 癌蛋白激活中的新作用，其功能是实体瘤肿瘤发生过程中不依赖锚定生长所必需的。我们的数据显示了 PR55α 对 YAP 的两条调节线：（1） PR55α 抑制 MOB1 触发的 LATS1/2 激酶自激活，LATS1/2 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保留来抑制 YAP，以及 （2） PR55α 直接与 YAP 本身相互作用并调节 YAP。因此，PR55α 对于 YAP 促进的基因转录以及不依赖锚定的生长至关重要，其中 YAP 起关键作用。 总之，目前的研究结果证明了一种基于 PR55α 调节的 PP2A 磷酸酶的新型 YAP 激活机制。