Integrin-mediated Protein Kinase A Activation at the Leading Edge of Migrating Cells Running Head: Integrins Specify Localized PKA Activation

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 α4β1 or α5β1 and an intact actin cytoskeleton. α4 integrins are Type I PKA-specific A-Kinase Anchoring Proteins (AKAPs) and we now find that Type I PKA is important for localization of α4β1 integrin-mediated PKA activation at the leading edge. Accumulation of 3’ phosphorylated phospho-inositides (PtdIns(3,4,5)P 5