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Molecular and Cellular Biology, February 2008, p. 1274-1284, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01139-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Localization to the Cortical Cytoskeleton Is Necessary for Nf2/Merlin-Dependent Epidermal Growth Factor Receptor Silencing{triangledown} ,{dagger}

Banumathi K. Cole,1 Marcello Curto,1 Annie W. Chan,1,2 and Andrea I. McClatchey1*

MGH Center for Cancer Research and Harvard Medical School, Department of Pathology, Charlestown, Massachusetts 02129,1 MGH Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts 021142

Received 26 June 2007/ Returned for modification 15 August 2007/ Accepted 4 December 2007

Merlin, the product of the NF2 tumor suppressor gene, is closely related to the ERM (ezrin, radixin, moesin) proteins, which provide anchorage between membrane proteins and the underlying cortical cytoskeleton; all four proteins are members of the band 4.1 superfamily. Despite their similarity, the subcellular distributions and functional properties of merlin and the ERM proteins are largely distinct. Upon cell-cell contact merlin prevents internalization of and signaling from the epidermal growth factor receptor (EGFR) by sequestering it into an insoluble membrane compartment. Here we show that the extreme amino (N) terminus directs merlin biochemically to an insoluble membrane compartment and physically to the cortical actin network, with a marked concentration along cell-cell boundaries. This insoluble-membrane distribution is required for the growth-suppressing function of merlin and for the functional association of merlin with EGFR and other membrane receptors. Our data support a model whereby locally activated merlin sequesters membrane receptors such as EGFR at the cortical network, contributing to the long-held observation that the cortical actin cytoskeleton can control the lateral mobility of and signaling from certain membrane receptors.

* Corresponding author. Mailing address: Massachusetts General Hospital East, 149 CNY 13th St., Charlestown, MA 02129. Phone: (617) 726-5648. Fax: (617) 726-7808. E-mail: mcclatch{at}helix.mgh.harvard.edu

{triangledown} Published ahead of print on 17 December 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, February 2008, p. 1274-1284, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01139-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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