State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
PLoS One. 2011;6(9):e24288. doi: 10.1371/journal.pone.0024288. Epub 2011 Sep 1.
The Hippo/MST1 signaling pathway plays an important role in the regulation of cell proliferation and apoptosis. As a major downstream target of the Hippo/MST1 pathway, YAP2 (Yes-associated protein 2) functions as a transcriptional cofactor that has been implicated in many biological processes, including organ size control and cancer development. MST1/Lats kinase inhibits YAP2's nuclear accumulation and transcriptional activity through inducing the phosphorylation at serine 127 and the sequential association with 14-3-3 proteins. However, the dephosphorylation of YAP2 is not fully appreciated.
METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2. Inhibition of PP1 by okadiac acid (OA) increases the phosphorylation at serine 127 and cytoplasmic translocation of YAP2 proteins, thereby mitigating its transcription activity. PP1A expression enhances YAP2's pro-survival capability and YAP2 knockdown sensitizes ovarian cancer cells to cisplatin treatment.
CONCLUSIONS/SIGNIFICANCE: Our findings define a novel molecular mechanism that YAP2 is positively regulated by PP1-mediated dephosphorylation in the cell survival.
Hippo/MST1 信号通路在调节细胞增殖和凋亡方面发挥着重要作用。作为 Hippo/MST1 通路的主要下游靶标，YAP2（Yes 相关蛋白 2）作为转录共激活因子发挥作用，与许多生物学过程有关，包括器官大小控制和癌症发展。MST1/Lats 激酶通过诱导丝氨酸 127 磷酸化和与 14-3-3 蛋白的连续结合，抑制 YAP2 的核积累和转录活性。然而，YAP2 的去磷酸化并未得到充分认识。
方法/主要发现：在本研究中，我们证明 PP1A（蛋白磷酸酶-1 的催化亚基）在体外和体内与 YAP2 相互作用并使其去磷酸化，PP1A 介导的去磷酸化诱导 YAP2 的核积累和转录激活。OA（Okadaic acid）抑制 PP1 增加丝氨酸 127 的磷酸化和 YAP2 蛋白的细胞质易位，从而减轻其转录活性。PP1A 的表达增强了 YAP2 的生存能力，而 YAP2 的敲低使卵巢癌细胞对顺铂治疗敏感。
结论/意义：我们的研究结果定义了一个新的分子机制，即 YAP2 通过细胞存活中的 PP1 介导的去磷酸化被正向调控。
