Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell. 2013 Sep 12;154(6):1342-55. doi: 10.1016/j.cell.2013.08.025. Epub 2013 Sep 5.
Although Merlin/NF2 was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. In contrast to the commonly depicted linear model of Merlin functioning through Hpo/Mst, here we show that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. We further show that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. Our findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction.
虽然 Merlin/NF2 作为神经纤维瘤病 II 型的肿瘤抑制因子被发现已有二十多年，但它的确切分子机制仍知之甚少。最近在果蝇中的研究通过将 Merlin 基因置于激酶 Hpo/Mst 的上游，揭示了 Merlin 与 Hippo 通路之间的潜在联系。与 Merlin 通过 Hpo/Mst 发挥作用的常见线性模型相反，我们在这里表明，在果蝇和哺乳动物中，Merlin 促进下游 Hippo 信号转导，而不激活 Hpo/Mst 的内在激酶活性。相反，Merlin 直接结合并募集效应激酶 Wts/Lats 到质膜。反过来，质膜募集促进 Hpo-Sav 激酶复合物对 Wts 的磷酸化。我们进一步表明，肌动蛋白细胞骨架的破坏促进 Merlin-Wts 相互作用，这表明 Merlin 参与了肌动蛋白介导的 Hippo 信号转导的调节。我们的发现阐明了 Merlin 的一个重要分子功能，并强调了质膜作为 Hippo 信号转导的关键亚细胞隔室。
