Royer Christophe, Koch Sofia, Qin Xiao, Zak Jaroslav, Buti Ludovico, Dudziec Ewa, Zhong Shan, Ratnayaka Indrika, Srinivas Shankar, Lu Xin
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
PLoS One. 2014 Oct 31;9(10):e111384. doi: 10.1371/journal.pone.0111384. eCollection 2014.
The Hippo pathway, by tightly controlling the phosphorylation state and activity of the transcription cofactors YAP and TAZ is essential during development and tissue homeostasis whereas its deregulation may lead to cancer. Recent studies have linked the apicobasal polarity machinery in epithelial cells to components of the Hippo pathway and YAP and TAZ themselves. However the molecular mechanism by which the junctional pool of YAP proteins is released and activated in epithelial cells remains unknown. Here we report that the tumour suppressor ASPP2 forms an apical-lateral polarity complex at the level of tight junctions in polarised epithelial cells, acting as a scaffold for protein phosphatase 1 (PP1) and junctional YAP via dedicated binding domains. ASPP2 thereby directly induces the dephosphorylation and activation of junctional YAP. Collectively, this study unearths a novel mechanistic paradigm revealing the critical role of the apical-lateral polarity complex in activating this localised pool of YAP in vitro, in epithelial cells, and in vivo, in the murine colonic epithelium. We propose that this mechanism may commonly control YAP functions in epithelial tissues.
河马通路通过严格控制转录辅因子YAP和TAZ的磷酸化状态及活性，在发育和组织稳态过程中至关重要，而其失调可能导致癌症。最近的研究已将上皮细胞中的顶-基极性机制与河马通路的组分以及YAP和TAZ本身联系起来。然而，YAP蛋白在紧密连接处的释放和激活的分子机制在很大程度上仍不清楚。在此，我们报道肿瘤抑制因子ASPP2在极化上皮细胞的紧密连接处形成顶-侧极性复合物，通过专用结合结构域作为蛋白磷酸酶1（PP1）和连接蛋白YAP的支架。ASPP2由此直接诱导连接蛋白YAP的去磷酸化和激活。总体而言，本研究揭示了一种新的机制范式，揭示了顶-侧极性复合物在体外、上皮细胞中和体内小鼠结肠上皮中激活YAP局部池的关键作用。我们认为这种机制可能普遍控制上皮组织中YAP的功能。
