Published 17 July 2006. doi:10.1083/jcb.200510062
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 2, 277-288
An inhibitory role for FAK in regulating proliferation: a link between limited adhesion and RhoA-ROCK signaling
Dana M. Pirone1,3,
Wendy F. Liu1,3,
Sami Alom Ruiz1,3,
Lin Gao3,
Srivatsan Raghavan1,3,
Christopher A. Lemmon1,2,
Lewis H. Romer2, and
Christopher S. Chen1,3
1 Department of Biomedical Engineering, 2 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 3 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104
Correspondence to Christopher S. Chen: chrischen{at}seas.upenn.edu
Focal adhesion kinase (FAK) transduces cell adhesion to the extracellular matrix into proliferative signals. We show that FAK overexpression induced proliferation in endothelial cells, which are normally growth arrested by limited adhesion. Interestingly, displacement of FAK from adhesions by using a FAK–/– cell line or by expressing the C-terminal fragment FRNK also caused an escape of adhesion-regulated growth arrest, suggesting dual positive and negative roles for FAK in growth regulation. Expressing kinase-dead FAK-Y397F in FAK–/– cells prevented uncontrolled growth, demonstrating the antiproliferative function of inactive FAK. Unlike FAK overexpression–induced growth, loss of growth control in FAK–/– or FRNK-expressing cells increased RhoA activity, cytoskeletal tension, and focal adhesion formation. ROCK inhibition rescued adhesion-dependent growth control in these cells, and expression of constitutively active RhoA or ROCK dysregulated growth. These findings demonstrate the ability of FAK to suppress and promote growth, and underscore the importance of multiple mechanisms, even from one molecule, to control cell proliferation.
Abbreviations used in this paper: EC, endothelial cell; FAT, focal adhesion targeting; GAP, GTPase-activating protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mPAD, microfabricated post array detector; PDMS, poly(dimethylsiloxane).
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