Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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14-3-3 Proteins / metabolism
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A Kinase Anchor Proteins / metabolism
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Actinin / metabolism
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing
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Animals
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Binding, Competitive
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Calcineurin / metabolism*
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Calcineurin Inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
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Cell Line
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Cell Nucleus / metabolism*
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Cytoskeletal Proteins
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Enzyme Activation
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Humans
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Mice
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Microfilament Proteins / metabolism*
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Muscle Proteins / metabolism
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Myoblasts / cytology
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Myoblasts / enzymology
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / enzymology*
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Nuclear Proteins / metabolism
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Phosphoserine / metabolism
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Phosphothreonine / metabolism
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Protein Binding
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Protein Transport
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Rats
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Signal Transduction
Substances
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14-3-3 Proteins
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A Kinase Anchor Proteins
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AKAP6 protein, human
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Adaptor Proteins, Signal Transducing
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Calcineurin Inhibitors
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Cytoskeletal Proteins
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Microfilament Proteins
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Muscle Proteins
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Nuclear Proteins
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PDE4DIP protein, human
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Synpo2 protein, mouse
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Actinin
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Phosphothreonine
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Phosphoserine
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Cyclic AMP-Dependent Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcineurin