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Published 1 August 2005. doi:10.1083/jcb.200502090
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 3, 465-476
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Article

Essential role of CIB1 in regulating PAK1 activation and cell migration



Tina M. Leisner1,2, Mingjuan Liu1, Zahara M. Jaffer4, Jonathan Chernoff4, and Leslie V. Parise1,2,3

1 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
3 Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
4 Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111

Correspondence to Leslie V. Parise: parise{at}med.unc.edu

p21-activated kinases (PAKs) regulate many cellular processes, including cytoskeletal rearrangement and cell migration. In this study, we report a direct and specific interaction of PAK1 with a 22-kD Ca2+-binding protein, CIB1, which results in PAK1 activation both in vitro and in vivo. CIB1 binds to PAK1 within discrete regions surrounding the inhibitory switch domain in a calcium-dependent manner, providing a potential mechanism of CIB1-induced PAK1 activation. CIB1 overexpression significantly decreases cell migration on fibronectin as a result of a PAK1-and LIM kinase–dependent increase in cofilin phosphorylation. Conversely, the RNA interference–mediated depletion of CIB1 increases cell migration and reduces normal adhesion-induced PAK1 activation and cofilin phosphorylation. Together, these results demonstrate that endogenous CIB1 is required for regulated adhesion-induced PAK1 activation and preferentially induces a PAK1-dependent pathway that can negatively regulate cell migration. These results point to CIB1 as a key regulator of PAK1 activation and signaling.

Abbreviations used in this paper: ca, constitutively active; DN, dominant negative; FN, fibronectin; HEK, human embryonic kidney; IS, inhibitory switch; kd, kinase dead; KI, kinase inhibitor; LIMK, Lin-11/Isl-1/Mec-3 kinase; MEF, mouse embryo fibroblast; NTA, nitrilotriacetic acid; PAK, p21-activated kinase; PBD, p21-binding domain; REF, rat embryo fibroblast; si, short inhibitory.


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