Protein Kinase A Opposes the Phosphorylation-dependent Recruitment of Glycogen Synthase Kinase 3β to A-kinase Anchoring Protein 220
Copyright policy )Protein Kinase A Opposes the Phosphorylation-dependent Recruitment of Glycogen Synthase Kinase 3β to A-kinase Anchoring Protein 220
The proximity of an enzyme to its substrate can influence rate and magnitude of catalysis. A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Using a combination of molecular and cellular approaches we show that GSK3β phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3β and its substrate β-catenin in membrane ruffles. Interestingly, GSK3β can be released from the multienzyme complex in response to PKA phosphorylation on serine 9, which suppresses GSK3β activity. The signaling scaffold may enhance this regulatory mechanism, as AKAP220 has the capacity to anchor two PKA holoenzymes. Site 1 on AKAP220 (residues 610-623) preferentially interacts with RII, whereas site 2 (residues 1633-1646) exhibits a dual specificity for RI and RII. In vitro affinity measurements revealed that site 2 on AKAP220 binds RII with ∼10-fold higher affinity than site 1. Occupancy of both R subunit binding sites on AKAP220 could provide a mechanism to amplify local cAMP responses and enable cross-talk between PKA and GSK3β.
- The Arctic University of Norway Norway
- University of Mary United States
- University of Washington United States
- Howard Hughes Medical Institute United States
Binding Sites, Glycogen Synthase Kinase 3 beta, Molecular Sequence Data, A Kinase Anchor Proteins, Epithelial Cells, Cyclic AMP-Dependent Protein Kinases, Protein Structure, Secondary, Cell Line, Glycogen Synthase Kinase 3, Mice, HEK293 Cells, Gene Expression Regulation, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Phosphorylation, Genetic Engineering, Holoenzymes, Protein Binding
Binding Sites, Glycogen Synthase Kinase 3 beta, Molecular Sequence Data, A Kinase Anchor Proteins, Epithelial Cells, Cyclic AMP-Dependent Protein Kinases, Protein Structure, Secondary, Cell Line, Glycogen Synthase Kinase 3, Mice, HEK293 Cells, Gene Expression Regulation, Animals, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Phosphorylation, Genetic Engineering, Holoenzymes, Protein Binding
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