Calsarcins, a novel family of sarcomeric calcineurin-binding proteins.

The calcium- and calmodulin-dependent protein phosphatase calcineurin has been implicated in the transduction of signals that control the hypertrophy of cardiac muscle and slow fiber gene expression in skeletal muscle. To identify proteins that mediate the effects of calcineurin on striated muscles, we used the calcineurin catalytic subunit in a two-hybrid screen for cardiac calcineurin-interacting proteins. From this screen, we discovered a member of a novel family of calcineurin-interacting proteins, termed calsarcins, which tether calcineurin to alpha-actinin at the z-line of the sarcomere of cardiac and skeletal muscle cells. Calsarcin-1 and calsarcin-2 are expressed in developing cardiac and skeletal muscle during embryogenesis, but calsarcin-1 is expressed specifically in adult cardiac and slow-twitch skeletal muscle, whereas calsarcin-2 is restricted to fast skeletal muscle. Calsarcins represent a novel family of sarcomeric proteins that link calcineurin with the contractile apparatus, thereby potentially coupling muscle activity to calcineurin activation.

[1]  Christopher C. Goodnow,et al.  Differential activation of transcription factors induced by Ca2+ response amplitude and duration , 1997, Nature.

[2]  E. Olson,et al.  Stimulation of Slow Skeletal Muscle Fiber Gene Expression by Calcineurin in Vivo * , 2000, The Journal of Biological Chemistry.

[3]  P. Burch,et al.  Desmin mutation responsible for idiopathic dilated cardiomyopathy. , 1999, Circulation.

[4]  E. Olson,et al.  Calcineurin Signaling and Muscle Remodeling , 2000, Cell.

[5]  E. Olson,et al.  Decoding calcium signals involved in cardiac growth and function , 2000, Nature Medicine.

[6]  E. Price,et al.  Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4 , 1996, Nature.

[7]  L. Langeberg,et al.  Coordination of Three Signaling Enzymes by AKAP79, a Mammalian Scaffold Protein , 1996, Science.

[8]  S. Snyder,et al.  Cain, A Novel Physiologic Protein Inhibitor of Calcineurin* , 1998, The Journal of Biological Chemistry.

[9]  E. Olson,et al.  Regulation of Microtubule Dynamics and Myogenic Differentiation by Murf, a Striated Muscle Ring-Finger Protein , 2000, The Journal of cell biology.

[10]  S. Daniels,et al.  Pathogenesis of dilated cardiomyopathy: molecular, structural, and population analyses in tropomodulin-overexpressing transgenic mice. , 1999, The American journal of pathology.

[11]  A. Musarò,et al.  IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1 , 1999, Nature.

[12]  J. Gilbert,et al.  Myotilin is mutated in limb girdle muscular dystrophy 1A. , 2000, Human molecular genetics.

[13]  C. Klee,et al.  Calcineurin: from structure to function. , 2000, Current topics in cellular regulation.

[14]  Y. Ono,et al.  Interaction of PKN with α-Actinin* , 1997, The Journal of Biological Chemistry.

[15]  J Staudinger,et al.  PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system , 1995, The Journal of cell biology.

[16]  S. Kempa,et al.  Indications for a Novel Muscular Dystrophy Pathway , 2000, Journal of Cell Biology.

[17]  J. Scott,et al.  A-kinase anchoring proteins: protein kinase A and beyond. , 2000, Current opinion in cell biology.

[18]  W. Zhu,et al.  A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. , 1998, Genes & development.

[19]  P. Hogan,et al.  Transcription factors of the NFAT family: regulation and function. , 1997, Annual review of immunology.

[20]  H. Youn,et al.  Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. , 1998, Immunity.

[21]  Rick B. Vega,et al.  A Protein Encoded within the Down Syndrome Critical Region Is Enriched in Striated Muscles and Inhibits Calcineurin Signaling* , 2000, The Journal of Biological Chemistry.

[22]  Minoru Hongo,et al.  MLP-Deficient Mice Exhibit a Disruption of Cardiac Cytoarchitectural Organization, Dilated Cardiomyopathy, and Heart Failure , 1997, Cell.

[23]  S. Ryu,et al.  Cardiac Phospholipase D2 Localizes to Sarcolemmal Membranes and Is Inhibited by α-Actinin in an ADP-ribosylation Factor-reversible Manner* , 2000, The Journal of Biological Chemistry.

[24]  S. Fields,et al.  A novel genetic system to detect protein–protein interactions , 1989, Nature.

[25]  L. Goatley,et al.  A viral mechanism for inhibition of the cellular phosphatase calcineurin. , 1998, Science.

[26]  E. Olson,et al.  From the sarcomere to the nucleus: role of genetics and signaling in structural heart disease. , 2000, Annual review of genomics and human genetics.

[27]  R. Lefkowitz,et al.  alpha-Actinin is a potent regulator of G protein-coupled receptor kinase activity and substrate specificity in vitro. , 2000, FEBS letters.

[28]  F. Muntoni,et al.  Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. , 1993, The New England journal of medicine.

[29]  K. Chien.  Genomic circuits and the integrative biology of cardiac diseases , 2000, Nature.

[30]  E. Olson,et al.  Capsulin: a novel bHLH transcription factor expressed in epicardial progenitors and mesenchyme of visceral organs , 1998, Mechanisms of Development.

[31]  E. Olson,et al.  MEF2 responds to multiple calcium‐regulated signals in the control of skeletal muscle fiber type , 2000, The EMBO journal.

[32]  L. Langeberg,et al.  Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. , 1995, Science.

[33]  K. Cunningham,et al.  A conserved family of calcineurin regulators. , 2000, Genes & development.

[34]  J. Molkentin,et al.  Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.