Weis Center for Research, 100 North Academy Avenue, Danville, PA 17822, USA.
Biochem J. 2010 Dec 15;432(3):461-72. doi: 10.1042/BJ20100870.
The Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2-ZO-2 complex could represent a target for cancer therapy.
Hippo 通路通过控制两种相反的过程：增殖和细胞凋亡，来调节器官的大小。YAP2（Yes 激酶相关蛋白 2）是 YAP 的三种同工型之一，是哺乳动物细胞 Hippo 通路的效应物，是一个含有 WW 结构域的转录共激活因子。除了 WW 结构域外，YAP2 的 C 末端还有一个 PDZ 结合基序。我们之前的研究表明，该基序对于 YAP2 在核内的定位以及促进细胞脱离和凋亡是必需的。在本研究中，我们发现紧密连接蛋白 ZO-2（封闭蛋白）利用其第一个 PDZ 结构域与 YAP2 形成复合物。内源性 ZO-2 和 YAP2 蛋白在核内共定位。我们还发现 ZO-2 促进 YAP2 的核定位和促凋亡功能，而 ZO-2 的这种活性依赖于 PDZ 结构域。本文首次报道了基于 PDZ 的核易位机制。此外，由于 Hippo 通路作为一种肿瘤抑制途径，YAP2-ZO-2 复合物可能成为癌症治疗的靶点。
