Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2

• Published in: Cell Vol. 154; no. 6; pp. 1342 - 1355
• Main Authors: Yin, Feng, Yu, Jianzhong, Zheng, Yonggang, Chen, Qian, Zhang, Nailing, Pan, Duojia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.09.2013
• Subjects: Amino Acid Sequence; Animals; Biological Evolution; Cell Membrane - metabolism; Cytoskeleton - metabolism; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; linear models; mammals; Mice; microfilaments; Molecular Sequence Data; Neurofibromin 2 - metabolism; phosphorylation; plasma membrane; plasma membranes; Protein Serine-Threonine Kinases - metabolism; Sequence Alignment; Signal Transduction
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.08.025

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. [Display omitted] •Merlin promotes Hippo signaling without stimulating the kinase activity of Hpo/Mst•Merlin promotes plasma membrane association of Wts/Lats through direct binding•Membrane targeting promotes Wts phosphorylation and tumor-suppressor activity•Distinct roles of Sav and Mer in membrane association of the Hippo kinase cassette The activation of Hippo by the tumor suppressor Merlin is not as linear as has been assumed; formation of a plasma membrane-localized complex including Sav and Wts/Lats with regulatory inputs from the actin cytoskeleton is demonstrated.