The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3? Interaction Protein (GSKIP) Regulates ?-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3?.

ABSTRACT: The A-kinase anchoring protein (AKAP) GSK3? interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3? (GSK3?). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3? are required for the regulation of ?-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ?-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ?-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ?-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3? facilitates control of the destabilizing phosphorylation of ?-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ?-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ?-catenin. The regulation of ?-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3?, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3? is a conserved GSK3? interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3? 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.

SUBMITTER: Dema A 

PROVIDER: S-EPMC5016695 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature