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Published 24 October 2005. doi:10.1083/jcb.200503165
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 2, 361-371
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Article

Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane



Tomoyo Okada, Miguel Lopez-Lago, and Filippo G. Giancotti

Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Correspondence to T. Okada: t-okada{at}ski.mskcc.org; or F. Giancotti: f-giancotti{at}ski.mskcc.org

Introduction of activated p21-activated kinase (PAK) is sufficient to release primary endothelial cells from contact inhibition of growth. Confluent cells display deficient activation of PAK and translocation of Rac to the plasma membrane at matrix adhesions. Targeting Rac to the plasma membrane rescues these cells from contact inhibition. PAK's ability to release human umbilical vein endothelial cells from contact inhibition is blocked by an unphosphorylatable form of its target Merlin, suggesting that PAK promotes mitogenesis by phosphorylating, and thus inactivating, Merlin. Merlin mutants, which are presumed to exert a dominant-negative effect, enable recruitment of Rac to matrix adhesions and promote mitogenesis in confluent cells. Small interference RNA–mediated knockdown of Merlin exerts the same effects. Dominant-negative Rac blocks PAK-mediated release from contact inhibition, implying that PAK functions upstream of Rac in this signaling pathway. These results provide a framework for understanding the tumor suppressor function of Merlin and indicate that Merlin mediates contact inhibition of growth by suppressing recruitment of Rac to matrix adhesions.

Abbreviations used in this paper: ERK, extracellular signal-related protein kinase; ERM, ezrin–radixin–moesin; FN, fibronectin; HUVEC, human umbilical vein endothelial cells; PAK, p21-activated kinase; PL, poly-L-lysine; RTK, receptor tyrosine kinase; SFM, serum-free medium; siRNA, small interference RNA; VE, vascular endothelial.


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