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

Mark C. Wilkes, Claire E. Repellin, Min Hong, Margarita Bracamonte, Sumedha G. Penheiter, Jean Paul Borg, Edward B Leof

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Abstract

Transforming growth factor beta (TGF-β) 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-β on mesenchymal cells, and yet it is not responsive to TGF-β 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-β 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-β signaling, they also show that Erbin controls Merlin tumor suppressor function by switching the functional valence of PAK2 binding.

Original languageEnglish (US)
Pages (from-to)433-444
Number of pages12
JournalDevelopmental Cell
Volume16
Issue number3
DOIs
StatePublished - Mar 17 2009

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ASJC Scopus subject areas

  • Developmental Biology

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