Oh H, Irvine K D
Department of Molecular Biology and Biochemistry, Waksman Institute, Howard Hughes Medical Institute, Rutgers The State University of New Jersey, Piscataway, NJ 8854, USA.
Oncogene. 2009 Apr 30;28(17):1916-27. doi: 10.1038/onc.2009.43. Epub 2009 Mar 30.
The co-activator Yorkie (Yki) mediates transcriptional regulation effected by the Drosophila Fat-Warts (Wts)-Hippo (Hpo) pathways. Yki is inhibited by Wts-mediated phosphorylation, and a Wts phosphorylation site at Ser168 has been identified. Here we identify two additional Wts phosphorylation sites on Yki, and examine the respective contribution of all three sites to Yki nuclear localization and activity. Our results show that although Ser168 is the most critical site, all three phosphorylation sites influence Yki localization and activity in vivo, and can be sites of regulation by Wts. Thus, investigations of the role of Yki and its mammalian homolog Yes-associated protein (YAP) in development and oncogenesis should include evaluations of additional sites. The WW domains of Yki are not required for its phosphorylation, but instead are positively required for its activity. We also identify two potential sites of phosphorylation by an unknown kinase, which could influence phosphorylation of Ser168 by Wts, suggesting that there are additional mechanisms for regulating Yki/YAP activity.
共激活因子Yorkie（Yki）介导由果蝇Fat-Warts（Wts）-Hippo（Hpo）信号通路所产生的转录调控。Yki受Wts介导的磷酸化作用抑制，并且已鉴定出位于丝氨酸168处的一个Wts磷酸化位点。在此，我们鉴定出Yki上另外两个Wts磷酸化位点，并研究了所有这三个位点对Yki核定位及活性的各自贡献。我们的结果表明，虽然丝氨酸168是最关键的位点，但所有这三个磷酸化位点在体内均影响Yki的定位和活性，并且均可作为Wts的调控位点。因此，对Yki及其哺乳动物同源物Yes相关蛋白（YAP）在发育和肿瘤发生中作用的研究应包括对其他位点的评估。Yki的WW结构域对其磷酸化并非必需，而是对其活性呈正向需求。我们还鉴定出两个可能被未知激酶磷酸化的位点，这可能影响Wts对丝氨酸168的磷酸化，提示存在调控Yki/YAP活性的其他机制。
