Anchored protein kinase A recruitment of active Rac GTPase |
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Authors: | Logue Jeremy S Whiting Jennifer L Tunquist Brian Langeberg Lorene K Scott John D |
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Affiliation: | From the ‡Howard Hughes Medical Institute, ;¶Department of Pharmacology, and ;the §Molecular and Cellular Biology Program, University of Washington School of Medicine, Seattle, Washington 98195 |
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Abstract: | Protein kinase A-anchoring proteins (AKAPs) influence fundamental cellular processes by directing the cAMP-dependent protein kinase (PKA) toward its intended substrates. In this report we describe the identification and characterization of a ternary complex of AKAP220, the PKA holoenzyme, and the IQ domain GTPase-activating protein 2 isoform (IQGAP2) that is enriched at cortical regions of the cell. Formation of an IQGAP2-AKAP220 core complex initiates a subsequent phase of protein recruitment that includes the small GTPase Rac. Biochemical and molecular biology approaches reveal that PKA phosphorylation of Thr-716 on IQGAP2 enhances association with the active form of the Rac GTPase. Cell-based experiments indicate that overexpression of an IQGAP2 phosphomimetic mutant (IQGAP2 T716D) enhances the formation of actin-rich membrane ruffles at the periphery of HEK 293 cells. In contrast, expression of a nonphosphorylatable IQGAP2 T716A mutant or gene silencing of AKAP220 suppresses formation of membrane ruffles. These findings imply that IQGAP2 and AKAP220 act synergistically to sustain PKA-mediated recruitment of effectors such as Rac GTPases that impact the actin cytoskeleton. |
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Keywords: | Adaptor Proteins Cyclic AMP (cAMP) Phosphorylation Enzymes Protein Kinase A (PKA) Signal Transduction A Kinase-anchoring Protein Compartmentalization |
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