MCB Accepts, published online ahead of print on 14 April 2008

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Mol. Cell. Biol. doi:10.1128/MCB.01532-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pak1 and Pak2 Mediate Tumor Cell Invasion Through Distinct Signaling Mechanisms

Salvatore J. Coniglio, Salvatore Zavarella, and Marc H. Symons^*

Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, New York, NY; The Feinstein Institute for Medical Research at North Shore-LIJ, and Department of Surgery, North Shore University Hospital, Manhasset, NY

^* To whom correspondence should be addressed. Email: msymons{at}nshs.edu.

Pak kinases are thought to play critical roles in cell migration and invasion. Here we analyze the roles of Pak1 and Pak2 in breast carcinoma cell invasion using transient transfection of siRNA. We find that although both Pak1 and Pak2 contribute to breast carcinoma invasion stimulated by heregulin, these roles are mediated by distinct signaling mechanisms. Thus, whereas depletion of Pak1 interferes with heregulin-mediated dephosphorylation of cofilin, depletion of Pak2 does not. Depletion of Pak1 also has a stronger inhibitory effect on lamellipodial protrusion than Pak2. Interestingly, Pak1 and Pak2 play opposite roles in regulating the phosphorylation of myosin light chain (MLC). Whereas depletion of Pak1 decreases phospho-MLC levels in heregulin-stimulated cells, depletion of Pak2 enhances MLC phosphorylation. Consistent with their opposite effects on MLC phosphorylation, Pak1 and Pak2 differentially modulate focal adhesions. Pak2-depleted cells display an increase in focal adhesion size, whereas in Pak1-depleted cells, focal adhesions fail to mature. We also found that depletion of Pak2, but not Pak1, enhances RhoA activity and that inhibition of RhoA signaling in Pak2-depleted cells decreases MLC phosphorylation and restores cell invasion. In summary, this work presents the first comprehensive analysis of functional differences between the Pak1 and Pak2 isoforms.

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