Back to Search
Start Over
Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo.
- Source :
-
Circulation research [Circ Res] 2010 Mar 19; Vol. 106 (5), pp. 880-90. Date of Electronic Publication: 2010 Jan 21. - Publication Year :
- 2010
-
Abstract
- Rationale: 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.<br />Objective: Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown.<br />Methods and 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.<br />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.
- Subjects :
- Actin Cytoskeleton metabolism
Adaptor Proteins, Signal Transducing metabolism
Amino Acid Sequence
Animals
COS Cells
Cardiomyopathies genetics
Cardiomyopathies physiopathology
Cattle
Chlorocebus aethiops
Cloning, Molecular
Computational Biology
Desmoplakins metabolism
Dogs
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Humans
Membrane Proteins metabolism
Mice
Microfilament Proteins metabolism
Molecular Sequence Data
Muscle Proteins genetics
Phosphoproteins metabolism
Protein Binding
Transfection
Two-Hybrid System Techniques
Zebrafish
Zonula Occludens-1 Protein
rho GTP-Binding Proteins metabolism
Cardiomyopathies metabolism
Muscle Proteins metabolism
Myocardial Contraction
Myocardium metabolism
Serum Response Factor metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 106
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 20093627
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.109.213256