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Vol. 19, Issue 11, 4930-4941, November 2008

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Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells

Chinten J. Lim^*,, Kristin H. Kain^*,,, Eugene Tkachenko^*, Lawrence E. Goldfinger^*,, Edgar Gutierrez^||, Michael D. Allen^¶, Alex Groisman^||, Jin Zhang^¶, and Mark H. Ginsberg^*

*Department of Medicine, University of California San Diego, La Jolla, CA 92093-0726; ^||Department of Physics, University of California San Diego, La Jolla, CA 92093-0374; and ^¶Department of Pharmacology and Molecular Sciences and Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

Submitted June 5, 2008; Revised August 12, 2008; Accepted September 3, 2008
Monitoring Editor: Jean E. Schwarzbauer

cAMP-dependent protein kinase A (PKA) is important in processes requiring localized cell protrusion, such as cell migration and axonal path finding. Here, we used a membrane-targeted PKA biosensor to reveal activation of PKA at the leading edge of migrating cells. Previous studies show that PKA activity promotes protrusion and efficient cell migration. In live migrating cells, membrane-associated PKA activity was highest at the leading edge and required ligation of integrins such as 4β1 or 5β1 and an intact actin cytoskeleton. 4 integrins are type I PKA-specific A-kinase anchoring proteins, and we now find that type I PKA is important for localization of 4β1 integrin-mediated PKA activation at the leading edge. Accumulation of 3' phosphorylated phosphoinositides [PtdIns(3,4,5)P₃] products of phosphatidylinositol 3-kinase (PI3-kinase) is an early event in establishing the directionality of migration; however, polarized PKA activation did not require PI3-kinase activity. Conversely, inhibition of PKA blocked accumulation of a PtdIns(3,4,5)P₃-binding protein, the AKT-pleckstrin homology (PH) domain, at the leading edge; hence, PKA is involved in maintaining cell polarity during migration. In sum, we have visualized compartment-specific PKA activation in migrating cells and used it to reveal that adhesion-mediated localized activation of PKA is an early step in directional cell migration.

These authors contributed equally to this work.

Present addresses: Sol Sherry Thrombosis Research Center and Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140;

Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2358.

Address correspondence to: Mark Ginsberg (mhginsberg{at}ucsd.edu)

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