title: Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2.
abstract: 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.
authors.affiliation: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yu
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Nailing
authors.initials: N
authors.lastname: Zhang
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D002462:Cell Membrane / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D025581:Neurofibromin 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D025581:Neurofibromin 2; D017346:Protein Serine-Threonine Kinases; C099885:merlin, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases