YAP1 Recruits c-Abl to Protect Angiomotin-Like 1 from Nedd4-Mediated Degradation

BackgroundTissue development and organ growth require constant remodeling of cell-cell contacts formed between epithelial cells. The Hippo signaling cascade curtails organ growth by excluding the transcriptional co-activator Yes Associated Protein 1 (YAP1) from the nucleus. Angiomotin family members recruit YAP1 to tight junctions [1], but whether YAP1 plays a specific role outside of the nucleus is currently unknown. Methodology/Principal FindingsThe present study demonstrates that the E3 ubiquitin ligase Nedd4.2 targets Angiomotin-like 1 (AMOTL1), a family member that promotes the formation of epithelial tight junctions, for ubiquitin-dependent degradation. Unexpectedly, YAP1 antagonizes the function of Nedd4.2, and protects AMOTL1 against Nedd4.2-mediated degradation. YAP1 recruits c-Abl, a tyrosine kinase that binds and phosphorylates Nedd4.2 on tyrosine residues, thereby modifying its ubiquitin-ligase activity. Conclusions/SignificanceOur results uncover a novel function for cytoplasmic YAP1. YAP1 recruits c-Abl to protect AMOTL1 against Nedd4.2-mediated degradation. Thus, YAP1, excluded from the nucleus, contributes to the maintenance of tight junctions.背景：组织发育与器官生长过程中，上皮细胞间形成的细胞-细胞连接需持续重塑。Hippo信号通路通过将转录共激活因子Yes相关蛋白1（Yes Associated Protein 1，YAP1）排除于细胞核外，从而抑制器官生长。血管动蛋白家族成员可将YAP1招募至紧密连接[1]，但目前尚不明确YAP1在细胞核外是否发挥特定功能。 研究方法与主要发现：本研究证实，E3泛素连接酶Nedd4.2可靶向促进上皮紧密连接形成的家族成员血管动蛋白样1（Angiomotin-like 1，AMOTL1），使其经泛素依赖途径降解。令人意外的是，YAP1可拮抗Nedd4.2的功能，保护AMOTL1免受Nedd4.2介导的降解。YAP1可招募酪氨酸激酶c-Abl，后者可结合Nedd4.2并在其酪氨酸残基上发生磷酸化，从而改变其泛素连接酶活性。 结论与意义：本研究结果揭示了细胞质YAP1的全新功能。YAP1通过招募c-Abl，保护AMOTL1免受Nedd4.2介导的降解。由此可见，被排除于细胞核外的YAP1可参与维持上皮紧密连接的稳态。