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大多数Ser / Thr磷酸酶活性。每个PP2A由催化亚基（C），支架亚基（A）和调节亚基（B）组成。虽然A和C亚基各自仅以两个高度保守的同工型存在，但大量B亚基不共享同源性，这决定了PP2A底物特异性和细胞定位。可以预料，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，这主要是基于药理学或生物学抑制剂对高度保守的A的功能丧失研究。或PP2A的C亚基。对特定途径的最新研究表明，某些PP2A复合物还具有促进肿瘤的功能。我们以前曾报道过PR55α（一种PP2A调节亚基）在致癌表型（包括胰腺癌细胞的体内致瘤性/转移性）的支持中的重要作用。在本报告中，我们阐明了PR55α调控的PP2A在YAP癌蛋白活化中的新作用，该功能是实体瘤发生期间锚定非依赖性生长所必需的。我们的数据显示了PR55α调节YAP的两条线：（1）PR55α抑制MOB1触发的LATS1 / 2激酶的自激活，LATS1 / 2激酶是河马途径的核心成员，通过诱导其蛋白酶体降解和胞质保留来抑制YAP；（2）PR55α直接与YAP互动并对其进行监管。因此，PR55α对于YAP促进的基因转录以及锚定非依赖性生长至关重要，其中YAP起着关键作用。