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Sci. Signal., 30 August 2011
Vol. 4, Issue 188, p. pt6
[DOI: 10.1126/scisignal.2002314]

PRESENTATIONS

Merlin/NF2 Functions Upstream of the Nuclear E3 Ubiquitin Ligase CRL4DCAF1 to Suppress Oncogenic Gene Expression

Jonathan Cooper1,*, Wei Li1,*, Liru You1, Gaia Schiavon1, Angela Pepe-Caprio1, Lu Zhou2, Ryohei Ishii3, Marco Giovannini4, C. Oliver Hanemann2, Stephen B. Long1, Hediye Erdjument-Bromage1, Pengbo Zhou3, Paul Tempst1, and Filippo G. Giancotti1{dagger}

1 Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2 Peninsula College of Medicine and Dentistry, University of Plymouth, Plymouth PL6 8BU, UK.
3 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
4 House Ear Institute, Center for Neural Tumor Research, Los Angeles, CA 90057, USA.
* These authors contributed equally to this work.

A presentation from the 50th Annual Meeting of the American Society for Cell Biology in Philadelphia, Pennsylvania, 11 to 15 December 2010.

Abstract: Integrin-mediated activation of PAK (p21-activated kinase) causes phosphorylation and inactivation of the FERM (4.1, ezrin, radixin, moesin) domain–containing protein Merlin, which is encoded by the NF2 (neurofibromatosis type 2) tumor suppressor gene. Conversely, cadherin engagement inactivates PAK, thus leading to accumulation of unphosphorylated Merlin. Current models imply that Merlin inhibits cell proliferation by inhibiting mitogenic signaling at or near the plasma membrane. We have recently shown that the unphosphorylated, growth-inhibiting form of Merlin accumulates in the nucleus and binds to the E3 ubiquitin ligase CRL4DCAF1 to suppress its activity. Depletion of DCAF1 blocks the hyperproliferation caused by inactivation of Merlin. Conversely, expression of a Merlin-insensitive DCAF1 mutant counteracts the antimitogenic effect of Merlin. Expression of Merlin or silencing of DCAF1 in Nf2-deficient cells induce an overlapping, tumor-suppressive program of gene expression. Mutations present in some tumors from NF2 patients disrupt Merlin’s ability to interact with or inhibit CRL4DCAF1. Lastly, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells isolated from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. Current studies are aimed at identifying the substrates and mechanism of action of CRL4DCAF1 and examining its role in NF2-dependent tumorigenesis in mouse models. We propose that Merlin mediates contact inhibition and suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1.

{dagger}Presenter and corresponding author. E-mail: f-giancotti{at}ski.mskcc.org

Citation: J. Cooper, W. Li, L. You, G. Schiavon, A. Pepe-Caprio, L. Zhou, R. Ishii, M. Giovannini, C. O. Hanemann, S. B. Long, H. Erdjument-Bromage, P. Zhou, P. Tempst, F. G. Giancotti, Merlin/NF2 Functions Upstream of the Nuclear E3 Ubiquitin Ligase CRL4DCAF1 to Suppress Oncogenic Gene Expression. Sci. Signal. 4, pt6 (2011).

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