Contact-dependent inhibition of EGFR signaling by Nf2/Merlin.
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.
Curto
Marcello
M
MGH Center for Cancer Research, Harvard Medical School Department of Pathology, Charlestown, MA 02129, USA.
Cole
Banumathi K
BK
Lallemand
Dominique
D
Liu
Ching-Hui
CH
McClatchey
Andrea I
AI
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D025581:Neurofibromin 2 / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism
D025581:Neurofibromin 2; D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D066246:ErbB Receptors