Journal
CIRCULATION RESEARCH
Volume 106, Issue 5, Pages 880-U120Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.109.213256
Keywords
myocytes; cardiac; cardiomyopathies; serum response factor
Funding
- Bundesministerium fur Bildung und Forschung, Germany (Nationales Genomforschungsnetz: NGFNplus) [01GS0108, 01GS0420, 01GS0836]
- NIH
- Donald W. Reynolds Center for Clinical Cardiovascular Research
- Robert A. Welch Foundation
Ask authors/readers for more resources
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. (Circ Res. 2010; 106: 880-890.)
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available