Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes.
Spatial and temporal resolution of intracellular signaling can be achieved by compartmentalizing transduction units. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Importin alpha binding and nuclear import of myopodin are regulated by serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Here we show that in the heart myopodin forms a Z-disc signaling complex with alpha-actinin, calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Phosphorylation of myopodin by protein kinase A (PKA) or CaMKII mediates 14-3-3 binding and nuclear import in myoblasts. Dephosphorylation of myopodin by calcineurin abrogates 14-3-3beta binding. Activation of PKA or inhibition of calcineurin in adult cardiac myocytes releases myopodin from the Z-disc and induces its nuclear import. The identification of myopodin as a direct target of PKA, CaMKII, and calcineurin defines a novel intracellular signaling pathway whereby changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart.
Faul
Christian
C
Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
Dhume
Ashwini
A
Schecter
Alison D
AD
Mundel
Peter
P
D048948:14-3-3 Proteins / Q000378:metabolism; D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000185:Actinin / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001667:Binding, Competitive; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology*; D009687:Nuclear Proteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction
D048948:14-3-3 Proteins; D054758:A Kinase Anchor Proteins; C093173:AKAP6 protein, human; D048868:Adaptor Proteins, Signal Transducing; D065095:Calcineurin Inhibitors; D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; C432971:PDE4DIP protein, human; C503980:Synpo2 protein, mouse; D000185:Actinin; D010769:Phosphothreonine; D010768:Phosphoserine; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin