Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 27, Issue 23, Pages 8215-8227Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00950-07
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Funding
- NHLBI NIH HHS [R01 HL073458, HL73458] Funding Source: Medline
- NIDA NIH HHS [DA18886, R01 DA018886] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062472, DK57683, R01 DK057683, DK062472] Funding Source: Medline
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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 14-3-3 beta 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.
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