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

Cell. 2013 Sep 12;154(6):1342-55. doi: 10.1016/j.cell.2013.08.025. Epub 2013 Sep 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Evolution
  • Cell Membrane / metabolism*
  • Cytoskeleton / metabolism
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Neurofibromin 2 / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Sequence Alignment
  • Signal Transduction*

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Neurofibromin 2
  • merlin, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila