Dual function of partitioning-defective 3 in the regulation of YAP phosphorylation and activation.
Dual function of partitioning-defective 3 in the regulation of YAP phosphorylation and activation.
复制标题
分配缺陷 3 在 YAP 磷酸化和激活调节中的双重功能
DOI：
10.1038/celldisc.2016.21
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Zhang P;Wang S;Wang S;Qiao J;Zhang L;Zhang Z;Chen Z
分区缺陷 3 (Par3) 是进化上保守的极性 PAR 复合物 (Par3/Par6/aPKC) 的关键组成部分，控制细胞极性并有助于细胞迁移、增殖和肿瘤发展。新的证据表明细胞极性蛋白作为调节 Hippo 通路的上游调节剂。然而，人们对 Par3 是否参与 Hippo 通路知之甚少。在这里，我们发现 Par3 和 YAP 动态地共定位于不同的亚细胞区室中；即膜、细胞质和细胞核，以细胞密度依赖的方式。有趣的是，Par3 敲低会促进 YAP 磷酸化，导致 MDCK 细胞中低细胞密度下 YAP 核易位的显着受损，但在高密度下则不会。此外，Par3 通过其第三个 PDZ 结构域直接与 YAP 的 PDZ 结合基序结合。这种相互作用是调节 YAP 磷酸化和核定位所必需的。从机制上讲，Par3 作为支架蛋白，与细胞质和细胞核中的 LATS1 和蛋白磷酸酶 1，α 亚基 (PP1A) 结合。 Par3促进LATS1和YAP的去磷酸化，从而增强YAP激活和细胞增殖。引人注目的是，我们还发现在PP1A敲低的情况下，Par3表达促进YAP过度磷酸化，从而导致YAP活性及其下游靶点受到抑制。 Par3 表达对不同肿瘤细胞系中 YAP 磷酸化和激活产生不同的影响。这些发现表明，Par3 可能在调节 Hippo 通路的激活方面发挥双重作用，其方式可能取决于细胞环境或细胞类型对细胞间接触和细胞极性信号的反应。
Partitioning-defective 3 (Par3), a key component of the evolutionarily conserved polarity PAR complex (Par3/Par6/aPKC), controls cell polarity and contributes to cell migration, proliferation and tumor development. Emerging evidence indicates that cell polarity proteins function as upstream modulators that regulate the Hippo pathway. However, little is known about Par3’s involvement in the Hippo pathway. Here, we find Par3 and YAP dynamically co-localize in different subcellular compartments; that is, the membrane, cytoplasm and nucleus, in a cell-density-dependent manner. Interestingly, Par3 knockdown promotes YAP phosphorylation, leading to a significant impairment of YAP nuclear translocation at low cell density, but not at high density, in MDCK cells. Furthermore, via its third PDZ domain, Par3 directly binds to the PDZ-binding motif of YAP. The interaction is required for regulating YAP phosphorylation and nuclear localization. Mechanistically, Par3, as a scaffold protein, associates with LATS1 and protein phosphatase 1, α subunit (PP1A) in the cytoplasm and nucleus. Par3 promotes the dephosphorylation of LATS1 and YAP, thus enhancing YAP activation and cell proliferation. Strikingly, we also find that under the condition of PP1A knockdown, Par3 expression promotes YAP hyperphosphorylation, leading to the suppression of YAP activity and its downstream targets. Par3 expression results in differential effects on YAP phosphorylation and activation in different tumor cell lines. These findings indicate that Par3 may have a dual role in regulating the activation of the Hippo pathway, in a manner possibly dependent on cellular context or cell type in response to cell–cell contact and cell polarity signals.