Abstract：
The Hippo pathway plays a crucial role in cell proliferation and differentiation during tumorigenesis, tissue homeostasis and early embryogenesis. Scaffold proteins from the ezrin-radixin-moesin (ERM) family, including neurofibromin 2 (NF2; Merlin), regulate the Hippo pathway through cell polarity. However, the mechanisms underlying Hippo pathway regulation via cell polarity in establishing outer cells remain unclear. In this study, we generated artificial Nf2 mutants in the N-terminal FERM domain (L64P) and examined Hippo pathway activity by assessing the subcellular localization of YAP1 in early embryos expressing these mutant mRNAs. The L64P-Nf2 mutant inhibited NF2 localization around the cell membrane, resulting in YAP1 cytoplasmic translocation in the polar cells. L64P-Nf2 expression also disrupted the apical centralization of both large tumor suppressor 2 (LATS2) and ezrin in the polar cells. Furthermore, Lats2 mutants in the FERM binding domain (L83K) inhibited YAP1 nuclear translocation. These findings demonstrate that NF2 subcellular localization mediates cell polarity establishment involving ezrin centralization. This study provides previously unreported insights into how the orchestration of the cell-surface components, including NF2, LATS2 and ezrin, modulates the Hippo pathway during cell polarization.
摘要：
Hippo通路在肿瘤发生过程中在细胞增殖和分化中起着至关重要的作用。组织稳态和早期胚胎发生。来自ezrin-radixin-moesin（ERM）家族的支架蛋白，包括神经纤维蛋白2（NF2；Merlin），通过细胞极性调节Hippo途径。然而,通过细胞极性调节Hippo通路在建立外部细胞中的潜在机制尚不清楚。在这项研究中,我们在N端FERM结构域(L64P)中产生了人工Nf2突变体,并通过评估YAP1在表达这些突变体mRNA的早期胚胎中的亚细胞定位来检查Hippo途径活性.L64P-Nf2突变体抑制NF2在细胞膜周围的定位，导致YAP1在极性细胞中的细胞质易位。L64P-Nf2的表达也破坏了大肿瘤抑制因子2（LATS2）和ezrin在极性细胞中的顶端集中。此外，FERM结合结构域(L83K)中的Lats2突变体抑制YAP1核易位。这些发现表明，NF2亚细胞定位介导了涉及ezrin集中化的细胞极性建立。这项研究提供了以前未报道的关于细胞表面成分的编排，包括NF2，LATS2和ezrin，在细胞极化过程中调节Hippo途径。
