title: Isoform-specific targeting of PKA to multivesicular bodies.
abstract: Although RII protein kinase A (PKA) regulatory subunits are constitutively localized to discrete cellular compartments through binding to A-kinase-anchoring proteins (AKAPs), RI subunits are primarily diffuse in the cytoplasm. In this paper, we report a novel AKAP-dependent localization of RIα to distinct organelles, specifically, multivesicular bodies (MVBs). This localization depends on binding to AKAP11, which binds tightly to free RIα or RIα in complex with catalytic subunit (holoenzyme). However, recruitment to MVBs occurs only with the release of PKA catalytic subunit (PKAc). This recruitment is reversed by reassociation with PKAc, and it is disrupted by the presence of AKAP peptides, mutations in the RIα AKAP-binding site, or knockdown of AKAP11. Cyclic adenosine monophosphate binding not only unleashes active PKAc but also leads to the targeting of AKAP11:RIα to MVBs. Therefore, we show that the RIα holoenzyme is part of a signaling complex with AKAP11, in which AKAP11 may direct RIα functionality after disassociation from PKAc. This model defines a new paradigm for PKA signaling.
authors.affiliation: Bioinformatics Program, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Michele E
authors.initials: ME
authors.lastname: Day
authors.forename: Guido M
authors.initials: GM
authors.lastname: Gaietta
authors.forename: Mira
authors.initials: M
authors.lastname: Sastri
authors.forename: Antonius
authors.initials: A
authors.lastname: Koller
authors.forename: Mason R
authors.initials: MR
authors.lastname: Mackey
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D057146:Multivesicular Bodies; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D054758:A Kinase Anchor Proteins; C099270:AKAP11 protein, human; D007527:Isoenzymes; D017868:Cyclic AMP-Dependent Protein Kinases