PUBLICATION
Myozap, a Novel Intercalated Disc Protein, Activates Serum Response Factor-Dependent Signaling and Is Required to Maintain Cardiac Function In Vivo
- Authors
- Seeger, T.S., Frank, D., Rohr, C., Will, R., Just, S., Grund, C., Lyon, R., Lüdde, M., Koegl, M., Sheikh, F., Rottbauer, W., Franke, W.W., Katus, H.A., Olson, E.N., and Frey, N.
- ID
- ZDB-PUB-100126-12
- Date
- 2010
- Source
- Circulation research 106(5): 880-890 (Journal)
- Registered Authors
- Just, Steffen, Rottbauer, Wolfgang
- Keywords
- myocytes, cardiac, cardiomyopathies, serum response factor
- MeSH Terms
-
- Actin Cytoskeleton/metabolism
- Adaptor Proteins, Signal Transducing/metabolism
- Amino Acid Sequence
- Animals
- COS Cells
- Cardiomyopathies/genetics
- Cardiomyopathies/metabolism*
- 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
- Muscle Proteins/metabolism*
- Myocardial Contraction*
- Myocardium/metabolism*
- Phosphoproteins/metabolism
- Protein Binding
- Serum Response Factor/metabolism*
- Signal Transduction*
- Transfection
- Two-Hybrid System Techniques
- Zebrafish
- Zonula Occludens-1 Protein
- rho GTP-Binding Proteins/metabolism
- PubMed
- 20093627 Full text @ Circ. Res.
Citation
Seeger, T.S., Frank, D., Rohr, C., Will, R., Just, S., Grund, C., Lyon, R., Lüdde, M., Koegl, M., Sheikh, F., Rottbauer, W., Franke, W.W., Katus, H.A., Olson, E.N., and Frey, N. (2010) Myozap, a Novel Intercalated Disc Protein, Activates Serum Response Factor-Dependent Signaling and Is Required to Maintain Cardiac Function In Vivo. Circulation research. 106(5):880-890.
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. Objective: Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown. 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. 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping