Liu Olivia Xuan, Lin Lester Bocheng, Bunk Soumya, Chew Tiweng, Wu Selwin K, Motegi Fumio, Low Boon Chuan
Mechanobiology Institute, National University of Singapore, Singapore.
Department of Biological Sciences, National University of Singapore, Singapore.
FEBS J. 2025 Apr;292(7):1587-1601. doi: 10.1111/febs.17304. Epub 2024 Oct 27.
Contact inhibition of proliferation is a critical cell density control mechanism governed by the Hippo signalling pathway. The biochemical signalling underlying cell density-dependent cues regulating Hippo signalling and its downstream effectors, YAP, remains poorly understood. Here, we reveal that the tight junction protein ZO-2 is required for the contact-mediated inhibition of proliferation. We additionally determined that the well-established molecular players of this process, namely Hippo kinase LATS1 and YAP, are regulated by ZO-2 and that the scaffolding function of ZO-2 promotes the interaction with and phosphorylation of YAP by LATS1. Mechanistically, YAP is phosphorylated when ZO-2 brings LATS1 and YAP together via its SH3 and PDZ domains, respectively, subsequently leading to the cytoplasmic retention and inactivation of YAP. In conclusion, we demonstrate that ZO-2 maintains Hippo signalling pathway activation by promoting the stability of LATS1 to inactivate YAP.
增殖的接触抑制是一种由Hippo信号通路调控的关键细胞密度控制机制。调节Hippo信号及其下游效应因子YAP的细胞密度依赖性信号的生化信号仍知之甚少。在这里，我们揭示紧密连接蛋白ZO-2是接触介导的增殖抑制所必需的。我们还确定，这个过程中公认的分子参与者，即Hippo激酶LATS1和YAP，受ZO-2调控，并且ZO-2的支架功能促进LATS1与YAP的相互作用以及LATS1对YAP的磷酸化。从机制上讲，当ZO-2分别通过其SH3和PDZ结构域将LATS1和YAP聚集在一起时，YAP会被磷酸化，随后导致YAP在细胞质中滞留并失活。总之，我们证明ZO-2通过促进LATS1的稳定性来使YAP失活，从而维持Hippo信号通路的激活。
