title: Anchored protein kinase A recruitment of active Rac GTPase.
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.
authors: Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, Washington 98195, USA.
authors: Jeremy S
authors: JS
authors: Logue
authors: Jennifer L
authors: JL
authors: Whiting
authors: Brian
authors: B
authors: Tunquist
authors: Lorene K
authors: LK
authors: Langeberg
authors: John D
authors: JD
authors: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000737:chemistry / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
chemical_list: D054758:A Kinase Anchor Proteins; D000199:Actins; C560627:Akap11 protein, mouse; C101002:IQGAP2 protein, human; D020703:ras GTPase-Activating Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D020744:rac GTP-Binding Proteins