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Published online January 14, 2008
doi:10.1083/jcb.200708194
The Journal of Cell Biology, Vol. 180, No. 1, 187-203
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Lim et al.
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Article

 PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility

Yangmi Lim1, Ssang-Taek Lim1, Alok Tomar1, Margaret Gardel2, Joie A. Bernard-Trifilo3, Xiao Lei Chen1, Sean A. Uryu1, Rafaela Canete-Soler4, Jinbin Zhai4, Hong Lin4, William W. Schlaepfer4, Perihan Nalbant5, Gary Bokoch5, Dusko Ilic6, Clare Waterman-Storer7, and David D. Schlaepfer1

1 Department of Reproductive Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093
2 Department of Physics, University of Chicago, Chicago, IL 60637
3 Millipore Biosciences, Temecula, CA 92590
4 Division of Neuropathology, University of Pennsylvania, Philadelphia, PA 19104
5 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
6 StemLifeLine Inc., San Carlos, CA 94070
7 Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892

Correspondence to David D. Schlaepfer: dschlaepfer{at}ucsd.edu

Integrin binding to matrix proteins such as fibronectin (FN) leads to formation of focal adhesion (FA) cellular contact sites that regulate migration. RhoA GTPases facilitate FA formation, yet FA-associated RhoA-specific guanine nucleotide exchange factors (GEFs) remain unknown. Here, we show that proline-rich kinase-2 (Pyk2) levels increase upon loss of focal adhesion kinase (FAK) in mouse embryonic fibroblasts (MEFs). Additionally, we demonstrate that Pyk2 facilitates deregulated RhoA activation, elevated FA formation, and enhanced cell proliferation by promoting p190RhoGEF expression. In normal MEFs, p190RhoGEF knockdown inhibits FN-associated RhoA activation, FA formation, and cell migration. Knockdown of p190RhoGEF-related GEFH1 does not affect FA formation in FAK–/– or normal MEFs. p190RhoGEF overexpression enhances RhoA activation and FA formation in MEFs dependent on FAK binding and associated with p190RhoGEF FA recruitment and tyrosine phosphorylation. These studies elucidate a compensatory function for Pyk2 upon FAK loss and identify the FAK–p190RhoGEF complex as an important integrin-proximal regulator of FA formation during FN-stimulated cell motility.

Y. Lim, S.-T. Lim, and A. Tomar contributed equally to this paper.

Y. Lim's present address is Mogam Biotechnology Research Institute, Yong-In, Korea 449-799.

Abbreviations used in this paper: Ad, adenoviral; FA, focal adhesion; FN, fibronectin; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GST-RBD, GST–Rhotekin Rho binding domain; MEF, mouse embryonic fibroblast; PTK, protein tyrosine kinase; Pyk2, proline-rich kinase 2; Scr, scrambled; shRNA, short hairpin RNA; TA, tetracycline transactivator; WT, wild type.


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