NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin.
The proliferation of normal cells is inhibited at confluence, but the molecular basis of this phenomenon, known as contact-dependent inhibition of proliferation, is unclear. We previously identified the neurofibromatosis type 2 (NF2) tumor suppressor Merlin as a critical mediator of contact-dependent inhibition of proliferation and specifically found that Merlin inhibits the internalization of, and signaling from, the epidermal growth factor receptor (EGFR) in response to cell contact. Merlin is closely related to the membrane-cytoskeleton linking proteins Ezrin, Radixin, and Moesin, and localization of Merlin to the cortical cytoskeleton is required for contact-dependent regulation of EGFR. We show that Merlin and Ezrin are essential components of a mechanism whereby mechanical forces associated with the establishment of cell-cell junctions are transduced across the cell cortex via the cortical actomyosin cytoskeleton to control the lateral mobility and activity of EGFR, providing novel insight into how cells inhibit mitogenic signaling in response to cell contact.
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Harvard Medical School, Boston, MA 02115.
Christine
C
Chiasson-MacKenzie
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Harvard Medical School, Boston, MA 02115.
Zachary S
ZS
Morris
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Quentin
Q
Baca
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Harvard Medical School, Boston, MA 02115.
Brett
B
Morris
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Harvard Medical School, Boston, MA 02115.
Joanna K
JK
Coker
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
Rossen
R
Mirchev
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 BioMEMs Resource Center, Massachusetts General Hospital, Charlestown, MA 02129.
Anne E
AE
Jensen
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 BioMEMs Resource Center, Massachusetts General Hospital, Charlestown, MA 02129.
Thomas
T
Carey
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 BioMEMs Resource Center, Massachusetts General Hospital, Charlestown, MA 02129 Department of Medicine, Harvard Medical School, Boston, MA 02115.
Shannon L
SL
Stott
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
David E
DE
Golan
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Massachusetts General Hospital, Charlestown, MA 02129 Department of Pathology, Harvard Medical School, Boston, MA 02115 mcclatch@helix.mgh.harvard.edu.
Andrea I
AI
McClatchey
D008841:Actin Cytoskeleton / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D003260:Contact Inhibition / Q000235:genetics / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D007365:Intercellular Junctions / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D013314:Stress, Mechanical; D000099149:Ezrin
D000205:Actomyosin; D003598:Cytoskeletal Proteins; D066246:ErbB Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025581:Neurofibromin 2; D024507:Nonmuscle Myosin Type IIA; D034741:RNA, Small Interfering; D000099149:Ezrin; C071058:moesin; C071776:radixin; C541485:EGFR protein, mouse