Association of an A-kinase-anchoring protein signaling scaffold with cadherin adhesion molecules in neurons and epithelial cells.
A-kinase-anchoring protein (AKAP) 79/150 organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin that regulates phosphorylation pathways underlying neuronal long-term potentiation and long-term depression (LTD) synaptic plasticity. AKAP79/150 postsynaptic targeting requires three N-terminal basic domains that bind F-actin and acidic phospholipids. Here, we report a novel interaction of these domains with cadherin adhesion molecules that are linked to actin through beta-catenin (beta-cat) at neuronal synapses and epithelial adherens junctions. Mapping the AKAP binding site in cadherins identified overlap with beta-cat binding; however, no competition between AKAP and beta-cat binding to cadherins was detected in vitro. Accordingly, AKAP79/150 exhibited polarized localization with beta-cat and cadherins in epithelial cell lateral membranes, and beta-cat was present in AKAP-cadherin complexes isolated from epithelial cells, cultured neurons, and rat brain synaptic membranes. Inhibition of epithelial cell cadherin adhesion and actin polymerization redistributed intact AKAP-cadherin complexes from lateral membranes to intracellular compartments. In contrast, stimulation of neuronal pathways implicated in LTD that depolymerize postsynaptic F-actin disrupted AKAP-cadherin interactions and resulted in loss of the AKAP, but not cadherins, from synapses. This neuronal regulation of AKAP79/150 targeting to cadherins may be important in functional and structural synaptic modifications underlying plasticity.
Gorski
Jessica A
JA
Department of Pharmacology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Gomez
Lisa L
LL
Scott
John D
JD
Dell'Acqua
Mark L
ML
D054758:A Kinase Anchor Proteins; D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D002448:Cell Adhesion; D016764:Cell Polarity; D002478:Cells, Cultured; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; D015820:Cadherins; D016194:Receptors, N-Methyl-D-Aspartate; D019703:Calcineurin