Functional properties of the titin/connectin-associated proteins, the muscle-specific RING finger proteins (MURFs), in striated muscle

The efficient functioning of striated muscle is dependent upon the proper alignment and coordinated activities of several cytoskeletal networks including myofibrils, microtubules, and intermediate filaments. However, the exact molecular mechanisms dictating their cooperation and contributions during muscle differentiation and maintenance remain unknown. Recently, the muscle specific RING finger (MURF) family members have established themselves as excellent candidates for linking myofibril components (including the giant, multi-functional protein, titin/connectin), with microtubules, intermediate filaments, and nuclear factors. MURF-1, the only family member expressed throughout development, has been implicated in several studies as an ubiquitin ligase that is upregulated in response to multiple stimuli during muscle atrophy. Cell culture studies suggest that MURF-1 specifically has a role in maintaining titin M-line integrity and yeast two-hybrid studies point toward its participation in muscle stress response pathways and gene expression. MURF-2 is developmentally down-regulated and is assembled at the M-line region of the sarcomere and with microtubules. Functionally, its expression is critical for maintenance of the sarcomeric M-line region, specific populations of stable microtubules, desmin and vimentin intermediate filaments, as well as for myoblast fusion and differentiation. A recent study also links MURF-2 to a titin kinase-based protein complex that is reportedly activated upon mechanical signaling. Finally, MURF-3 is developmentally upregulated, associates with microtubules, the sarcomeric M-line (this report) and Z-line, and is required for microtubule stability and myogenesis. Here, we focus on the biochemical and functional properties of this intriguing family of muscle proteins, and discuss how they may tie together titin-mediated myofibril signaling pathways (perhaps involving the titin kinase domain), biomechanical signaling, the muscle stress response, and gene expression.

[1]  S. Labeit,et al.  Towards a molecular understanding of titin. , 1992, The EMBO journal.

[2]  G Cooper,et al.  Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium. , 1993, Science.

[3]  J. Thissen,et al.  Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection , 2003, FEBS letters.

[4]  Hsin C. Lin,et al.  Insulin-like Growth Factor-1 ( IGF-1 ) Inversely Regulates Atrophy-induced Genes via the Phosphatidylinositol 3-Kinase / Akt / Mammalian Target of Rapamycin ( PI 3 K / Akt / mTOR ) Pathway * , 2005 .

[5]  A. Means,et al.  Regulatory and structural motifs of chicken gizzard myosin light chain kinase. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C. Gregorio,et al.  Muscle-specific RING finger-1 interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1 , 2002, The Journal of cell biology.

[7]  Thomas Sejersen,et al.  The Kinase Domain of Titin Controls Muscle Gene Expression and Protein Turnover , 2005, Science.

[8]  W. Frontera,et al.  IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. , 2004, Cell.

[9]  M. Matsuo,et al.  Molecular Identification and Characterization of a Novel Nuclear Protein Whose Expression Is Up-regulated in Insulin-resistant Animals* , 2003, The Journal of Biological Chemistry.

[10]  Christian C Witt,et al.  MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination. , 2005, Journal of molecular biology.

[11]  F. Melchior,et al.  SUMO--nonclassical ubiquitin. , 2000, Annual review of cell and developmental biology.

[12]  Cam Patterson,et al.  Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  H. Sorimachi,et al.  Muscle-specific Calpain, p94, Responsible for Limb Girdle Muscular Dystrophy Type 2A, Associates with Connectin through IS2, a p94-specific Sequence (*) , 1995, The Journal of Biological Chemistry.

[14]  G. Gundersen,et al.  Stable, detyrosinated microtubules function to localize vimentin intermediate filaments in fibroblasts , 1995, The Journal of cell biology.

[15]  Paul Young,et al.  Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly , 2001, The Journal of cell biology.

[16]  A. Goldberg,et al.  IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. , 2004, American journal of physiology. Endocrinology and metabolism.

[17]  T. Gustafson,et al.  Hormonal regulation of myosin heavy chain and alpha-actin gene expression in cultured fetal rat heart myocytes. , 1987, The Journal of biological chemistry.

[18]  K. Pelin,et al.  Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. , 2001, Journal of molecular biology.

[19]  Y. Toyama,et al.  Effects of taxol and Colcemid on myofibrillogenesis. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Price,et al.  Molecular signaling pathways regulating muscle proteolysis during atrophy , 2005, Current opinion in clinical nutrition and metabolic care.

[21]  Eric Karsenti,et al.  Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING-finger protein , 2002, Journal of Cell Science.

[22]  K. Wang,et al.  Titin: major myofibrillar components of striated muscle. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[23]  G. Gill,et al.  SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? , 2004, Genes & development.

[24]  Siegfried Labeit,et al.  The NH2 Terminus of Titin Spans the Z-Disc: Its Interaction with a Novel 19-kD Ligand (T-cap) Is Required for Sarcomeric Integrity , 1998, The Journal of cell biology.

[25]  M. Gautel,et al.  Two immunoglobulin‐like domains of the Z‐disc portion of titin interact in a conformation‐dependent way with telethonin , 1998, FEBS letters.

[26]  K. Borden.  RING fingers and B-boxes: zinc-binding protein-protein interaction domains. , 1998, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[27]  Christian C Witt,et al.  Conditional Expression of Mutant M-line Titins Results in Cardiomyopathy with Altered Sarcomere Structure* , 2003, The Journal of Biological Chemistry.

[28]  G. Vassort,et al.  Microtubule disruption modulates Ca(2+) signaling in rat cardiac myocytes. , 2000, Circulation research.

[29]  K. Maruyama,et al.  Connectin, an elastic protein of muscle. A connectin-like protein from the plasmodium Physarum polycephalum. , 1980, Journal of biochemistry.

[30]  T. Kemp,et al.  Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein. , 2000, Genomics.

[31]  H. Sorimachi,et al.  A Novel Ligand for CD44 Is Serglycin, a Hematopoietic Cell Lineage-specific Proteoglycan , 1995, The Journal of Biological Chemistry.

[32]  Siegfried Labeit,et al.  Titins: Giant Proteins in Charge of Muscle Ultrastructure and Elasticity , 1995, Science.

[33]  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.

[34]  H. Saitoh,et al.  Functional Heterogeneity of Small Ubiquitin-related Protein Modifiers SUMO-1 versus SUMO-2/3* , 2000, The Journal of Biological Chemistry.

[35]  Y. Zou,et al.  CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. , 1997, Development.

[36]  Hsin C. Lin,et al.  Insulin-like Growth Factor-1 (IGF-1) Inversely Regulates Atrophy-induced Genes via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) Pathway* , 2005, Journal of Biological Chemistry.

[37]  B. Russell,et al.  Microtubules are needed for dispersal of alpha-myosin heavy chain mRNA in rat neonatal cardiac myocytes. , 1998, Journal of molecular and cellular cardiology.

[38]  Siegfried Labeit,et al.  The giant protein titin: a major player in myocardial mechanics, signaling, and disease. , 2004, Circulation research.

[39]  W. Frontera,et al.  IKKβ/NF-κB Activation Causes Severe Muscle Wasting in Mice , 2004, Cell.

[40]  L. Kedes,et al.  A Novel Cardiac-Restricted Target for Doxorubicin , 1997, The Journal of Biological Chemistry.

[41]  John Trinick,et al.  Properties of Titin Immunoglobulin and Fibronectin-3 Domains* , 2004, Journal of Biological Chemistry.

[42]  G. Gundersen,et al.  Generation of a stable, posttranslationally modified microtubule array is an early event in myogenic differentiation , 1989, The Journal of cell biology.

[43]  J. Vigoreaux,et al.  Drosophila has a twitchin/titin-related gene that appears to encode projectin. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[44]  W. Linke,et al.  A spring tale: new facts on titin elasticity. , 1998, Biophysical journal.

[45]  H. Ishikawa,et al.  The distribution and arrangement of microtubules in mammalian skeletal muscle fibers. , 1991, Cell structure and function.

[46]  T. Obinata,et al.  Distribution of microtubules and other cytoskeletal filaments during myotube elongation as revealed by fluorescence microscopy , 1988, Cell and Tissue Research.

[47]  I. Klein.  Colchicine stimulates the rate of contraction of heart cells in culture. , 1983, Cardiovascular research.

[48]  A. Takeshita,et al.  Microtubules are involved in early hypertrophic responses of myocardium during pressure overload. , 1998, The American journal of physiology.

[49]  K. Borden.  RING domains: master builders of molecular scaffolds? , 2000, Journal of molecular biology.

[50]  C. Liew,et al.  A Novel Human Striated Muscle RING Zinc Finger Protein, SMRZ, Interacts with SMT3b via Its RING Domain* , 2001, The Journal of Biological Chemistry.

[51]  J. Sanger,et al.  Fishing out proteins that bind to titin , 2001, The Journal of cell biology.

[52]  M. Borodovsky,et al.  Titins in C.elegans with unusual features: coiled-coil domains, novel regulation of kinase activity and two new possible elastic regions. , 2002, Journal of molecular biology.

[53]  A. Prasad,et al.  Alteration of the C-terminal Amino Acid of Tubulin Specifically Inhibits Myogenic Differentiation* , 2002, The Journal of Biological Chemistry.

[54]  A. Goldberg,et al.  Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  I. Nonaka,et al.  Skeletal muscle gene expression in space‐flown rats , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[56]  C. Gregorio,et al.  Muscle-specific RING finger-2 (MURF-2) is important for microtubule, intermediate filament and sarcomeric M-line maintenance in striated muscle development , 2004, Journal of Cell Science.

[57]  Dietmar Labeit,et al.  The Complete Gene Sequence of Titin, Expression of an Unusual ≈700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking System , 2001 .

[58]  R. Fischmeister,et al.  Post-translational modifications of cardiac tubulin during chronic heart failure in the rat , 2002, Molecular and Cellular Biochemistry.

[59]  C. Gregorio,et al.  Mechanisms of thin filament assembly in embryonic chick cardiac myocytes: tropomodulin requires tropomyosin for assembly , 1995, The Journal of cell biology.

[60]  Coalignment of vimentin intermediate filaments with microtubules depends on kinesin , 1992 .

[61]  P. Freemont.  Ubiquitination: RING for destruction? , 2000, Current Biology.

[62]  Holly McDonough,et al.  Muscle ring finger protein-1 inhibits PKCε activation and prevents cardiomyocyte hypertrophy , 2004, The Journal of cell biology.

[63]  Christian C Witt,et al.  The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. , 2003, Journal of molecular biology.

[64]  G. Vassort,et al.  Microtubule Disruption by Colchicine Reversibly Enhances Calcium Signaling in Intact Rat Cardiac Myocytes , 2001, Circulation research.

[65]  G. Yancopoulos,et al.  The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. , 2004, Molecular cell.

[66]  S. Tapscott,et al.  Taxol induces postmitotic myoblasts to assemble interdigitating microtubule-myosin arrays that exclude actin filaments , 1981, The Journal of cell biology.

[67]  Henk Granzier,et al.  The sensitive giant: the role of titin-based stretch sensing complexes in the heart. , 2004, Trends in cell biology.

[68]  K. Borden.  RING fingers and B-boxes: zinc-binding protein-protein interaction domains. , 1998 .

[69]  Siegfried Labeit,et al.  Cardiac titin: an adjustable multi‐functional spring , 2002, The Journal of physiology.

[70]  J. Le Guennec,et al.  Modulation of Ca2+ Signaling by Microtubule Disruption in Rat Ventricular Myocytes and Its Dependence on the Ruptured Patch-Clamp Configuration , 2001, Circulation research.

[71]  K Weber,et al.  Molecular structure of the sarcomeric M band: mapping of titin and myosin binding domains in myomesin and the identification of a potential regulatory phosphorylation site in myomesin , 1997, The EMBO journal.

[72]  S. Lecker.  Ubiquitin‐protein ligases in muscle wasting: multiple parallel pathways? , 2003, Current opinion in clinical nutrition and metabolic care.

[73]  W. Linke,et al.  Varieties of elastic protein in invertebrate muscles. , 2002, Journal of muscle research and cell motility.

[74]  W. Linke,et al.  Section: Elastic Invertebrate Muscle Proteins; Varieties of elastic protein in invertebrate muscles , 2002, Journal of Muscle Research & Cell Motility.

[75]  R. Waterston,et al.  Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans , 1989, Nature.

[76]  F. Melchior,et al.  SUMO: ligases, isopeptidases and nuclear pores. , 2003, Trends in biochemical sciences.

[77]  D J Glass,et al.  Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy , 2001, Science.

[78]  John Trinick,et al.  Titin: properties and family relationships , 2003, Nature Reviews Molecular Cell Biology.