title: The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β.
abstract: The A-kinase anchoring protein (AKAP) GSK3β interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3β are required for the regulation of β-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets β-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause β-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the β-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3β facilitates control of the destabilizing phosphorylation of β-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on β-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with β-catenin. The regulation of β-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3β, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3β is a conserved GSK3β interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3β by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases.
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dema
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Micha Friedemann
authors.initials: MF
authors.lastname: Schröter
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Perets
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Skroblin
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Marie Christine
authors.initials: MC
authors.lastname: Moutty
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Veronika Anita
authors.initials: VA
authors.lastname: Deàk
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.affiliation: From the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany and the DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Oudenarder Strasse 16, 13347 Berlin, Germany enno.klussmann@mdc-berlin.de.
authors.forename: Enno
authors.initials: E
authors.lastname: Klussmann
mesh_terms: D054758:A Kinase Anchor Proteins; D000072283:A549 Cells; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000072417:Protein Domains; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; C099270:AKAP11 protein, human; C514503:GSKIP protein, human; D012097:Repressor Proteins; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: A-kinase anchoring protein (AKAP); GSKIP; Wnt signaling; beta-catenin (β-catenin); cell compartmentalization; glycogen synthase kinase 3 (GSK-3); glycogen synthase kinase 3β interaction protein; protein kinase