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Molecular basis for PP2A regulatory subunit B56 targeting in cardiomyocytes

¹Department of Internal Medicine, Division of Cardiology, and ²Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa; and ³Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, and the Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland

Submitted 15 January 2007 ; accepted in final form 3 April 2007

Protein phosphatase 2A (PP2A) is a multifunctional protein phosphatase with critical roles in excitable cell signaling. In the heart, PP2A function is linked with modulation of -adrenergic signaling and has been suggested to regulate key ion channels and transporters including Na/Ca exchanger, ryanodine receptor, inositol 1,4,5-trisphosphate receptor, and Na/K ATPase. Although many of the functional roles and molecular targets for PP2A in heart are known, little is established regarding the cellular pathways that localize specific PP2A isoform activities to subcellular sites. We report that the PP2A regulatory subunit B56 is an in vivo binding partner for ankyrin-B, an adapter protein required for normal subcellular localization of the Na/Ca exchanger, Na/K ATPase, and inositol 1,4,5-trisphosphate receptor. Ankyrin-B and B56 are colocalized and coimmunoprecipitate in primary cardiomyocytes. Using multiple strategies, we identified the structural requirements on B56 for ankyrin-B association as a 13 residue motif in the B56 COOH terminus not present in other B56 family polypeptides. Finally, we report that reduced ankyrin-B expression in primary ankyrin-B^+/– cardiomyocytes results in disorganized distribution of B56 that can be rescued by exogenous expression of ankyrin-B. These new data implicate ankyrin-B as a critical targeting component for PP2A in heart and identify a new class of signaling proteins targeted by ankyrin polypeptides.

cytoskeleton; trafficking; phosphatase

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