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

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

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  • 1Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA.

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.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
21481793
[PubMed - indexed for MEDLINE]
PMCID:
PMC3075552
Free PMC Article

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