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Published online June 4, 2007
doi:10.1083/jcb.200703010
The Journal of Cell Biology, Vol. 177, No. 5, 893-903
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Curto et al.
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Article

 Contact-dependent inhibition of EGFR signaling by Nf2/Merlin

Marcello Curto, Banumathi K. Cole, Dominique Lallemand, Ching-Hui Liu, and Andrea I. McClatchey

MGH Center for Cancer Research and Harvard Medical School Department of Pathology, Charlestown, MA 02129

Correspondence to Andrea I. McClatchey: mcclatch{at}helix.mgh.harvard.edu

The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a membrane/cytoskeleton-associated protein that mediates contact-dependent inhibition of proliferation. Here we show that upon cell–cell contact Merlin coordinates the processes of adherens junction stabilization and negative regulation of epidermal growth factor receptor (EGFR) signaling by restraining the EGFR into a membrane compartment from which it can neither signal nor be internalized. In confluent Nf2–/– cells, EGFR activation persists, driving continued proliferation that is halted by specific EGFR inhibitors. These studies define a new mechanism of tumor suppression, provide mechanistic insight into the poorly understood phenomenon of contact-dependent inhibition of proliferation, and suggest a therapeutic strategy for NF2-mutant tumors.

D. Lallemand's present address is INSERM U674, Fondation Jean Dausset-CEPH, 75010 Paris, France.

Abbreviations used in this paper: AJ, adherens junction; EGFR, epidermal growth factor receptor; ERM, Ezrin/Radixin/Moesin; FERM, four-point-one, ERM; LDC, liver-derived epithelial cell; MEF, mouse embryo fibroblast; NF2, neurofibromatosis type 2; OB, osteoblast; pTyr, phosphotyrosine; RTK, receptor tyrosine kinase; Tr-EGF, Texas red–conjugated EGF.


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