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Molecular and Cellular Biology, December 2007, p. 8215-8227, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00950-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Christian Faul,1 Ashwini Dhume,2 Alison D. Schecter,2 and Peter Mundel1*

Department of Medicine,1 Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York 100292

Received 29 May 2007/ Returned for modification 6 July 2007/ Accepted 22 September 2007

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 14-3-3ß 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.

* Corresponding author. Mailing address: Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1243, New York, NY 10029-6574. Phone: (212) 659-9332. Fax: (212) 849-2643. E-mail: peter.mundel{at}mssm.edu

{triangledown} Published ahead of print on 8 October 2007.

Molecular and Cellular Biology, December 2007, p. 8215-8227, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00950-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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