Erbin and the NF2 Tumor Suppressor Merlin Cooperatively Regulate Cell-Type-Specific Activation of PAK2 by TGF-beta

Dev Cell. 2009 Mar;16(3):433-44. doi: 10.1016/j.devcel.2009.01.009.

Abstract

Transforming growth factor beta (TGF-beta) family ligands are pleotropic proteins with diverse cell-type-specific effects on growth and differentiation. For example, PAK2 activation is critical for the proliferative/profibrotic action of TGF-beta on mesenchymal cells, and yet it is not responsive to TGF-beta in epithelial cells. We therefore investigated the regulatory constraints that prevent inappropriate PAK2 activation in epithelial cultures. The results show that the epithelial-enriched protein Erbin controls the function of the NF2 tumor suppressor Merlin by determining the output of Merlin's physical interactions with active PAK2. Whereas mesenchymal TGF-beta signaling induces PAK2-mediated inhibition of Merlin function in the absence of Erbin, Erbin/Merlin complexes bind and inactivate GTPase-bound PAK2 in epithelia. These results not only identify Erbin as a key determinant of epithelial resistance to TGF-beta signaling, they also show that Erbin controls Merlin tumor suppressor function by switching the functional valence of PAK2 binding.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Models, Biological
  • Neurofibromin 2 / genetics
  • Neurofibromin 2 / metabolism*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Protein Binding
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein

Substances

  • Carrier Proteins
  • Erbb2ip protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Neurofibromin 2
  • Neuropeptides
  • Rac1 protein, mouse
  • Recombinant Proteins
  • Transforming Growth Factor beta
  • Pak2 protein, mouse
  • p21-Activated Kinases
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein