A tight junction-associated Merlin-angiomotin complex mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions

Cancer Cell. 2011 Apr 12;19(4):527-40. doi: 10.1016/j.ccr.2011.02.017.

Abstract

The Merlin/NF2 tumor suppressor restrains cell growth and tumorigenesis by controlling contact-dependent inhibition of proliferation. We have identified a tight-junction-associated protein complex comprising Merlin, Angiomotin, Patj, and Pals1. We demonstrate that Angiomotin functions downstream of Merlin and upstream of Rich1, a small GTPase Activating Protein, as a positive regulator of Rac1. Merlin, through competitive binding to Angiomotin, releases Rich1 from the Angiomotin-inhibitory complex, allowing Rich1 to inactivate Rac1, ultimately leading to attenuation of Rac1 and Ras-MAPK pathways. Patient-derived Merlin mutants show diminished binding capacities to Angiomotin and are unable to dissociate Rich1 from Angiomotin or inhibit MAPK signaling. Depletion of Angiomotin in Nf2(-/-) Schwann cells attenuates the Ras-MAPK signaling pathway, impedes cellular proliferation in vitro and tumorigenesis in vivo.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Angiomotins
  • Animals
  • Cell Proliferation
  • GTPase-Activating Proteins / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins / physiology*
  • MAP Kinase Signaling System
  • Membrane Proteins / physiology*
  • Mice
  • Mice, SCID
  • Microfilament Proteins / physiology*
  • Molecular Sequence Data
  • Neurofibromin 2 / physiology*
  • Nucleoside-Phosphate Kinase / physiology
  • Peripheral Nerves / chemistry
  • Schwann Cells / chemistry
  • Signal Transduction / physiology*
  • Tight Junction Proteins
  • Tight Junctions / physiology*
  • Tumor Suppressor Proteins / physiology*
  • rac1 GTP-Binding Protein / physiology

Substances

  • AMOT protein, human
  • ARHGAP17 protein, human
  • Amot protein, mouse
  • Angiomotins
  • GTPase-Activating Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Microfilament Proteins
  • Neurofibromin 2
  • PATJ protein, human
  • Tight Junction Proteins
  • Tumor Suppressor Proteins
  • Nucleoside-Phosphate Kinase
  • MPP5 protein, human
  • rac1 GTP-Binding Protein