title: Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo.
abstract: BACKGROUND
  The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy.
  
  
  OBJECTIVE
  Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown.
  
  
  RESULTS
  Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens-1. In a yeast 2-hybrid screen for additional binding partners of Myozap we identified myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity. Myozap, in turn, strongly activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a Rho-dependent fashion. Finally, in vivo knockdown of the Myozap ortholog in zebrafish led to severe contractile dysfunction and cardiomyopathy.
  
  
  CONCLUSIONS
  Taken together, these findings reveal Myozap as a previously unrecognized component of a Rho-dependent signaling pathway that links the intercalated disc to cardiac gene regulation. Moreover, its subcellular localization and the observation of a severe cardiac phenotype in zebrafish, implicate Myozap in the pathogenesis of cardiomyopathy.
authors.affiliation: Professor of Internal Medicine and Cardiology, Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
authors.forename: Thalia S
authors.initials: TS
authors.lastname: Seeger
authors.forename: Derk
authors.initials: D
authors.lastname: Frank
authors.forename: Claudia
authors.initials: C
authors.lastname: Rohr
authors.forename: Rainer
authors.initials: R
authors.lastname: Will
authors.forename: Steffen
authors.initials: S
authors.lastname: Just
authors.forename: Christine
authors.initials: C
authors.lastname: Grund
authors.forename: Robert
authors.initials: R
authors.lastname: Lyon
authors.forename: Mark
authors.initials: M
authors.lastname: Luedde
authors.forename: Manfred
authors.initials: M
authors.lastname: Koegl
authors.forename: Farah
authors.initials: F
authors.lastname: Sheikh
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rottbauer
authors.forename: Werner W
authors.initials: WW
authors.lastname: Franke
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002417:Cattle; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D019295:Computational Biology; D051180:Desmoplakins / Q000378:metabolism; D004285:Dogs; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015027:Zebrafish; D062826:Zonula Occludens-1 Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495294:DSP protein, human; D051180:Desmoplakins; C495295:Dsp protein, mouse; C498552:MPRIP protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; C000594384:Myozap protein, mouse; D010750:Phosphoproteins; D026362:Serum Response Factor; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; C500243:p116Rip protein, mouse; D020741:rho GTP-Binding Proteins