| First Author | Seeger TS | Year | 2010 |
| Journal | Circ Res | Volume | 106 |
| Issue | 5 | Pages | 880-90 |
| PubMed ID | 20093627 | Mgi Jnum | J:170871 |
| Mgi Id | MGI:4947500 | Doi | 10.1161/CIRCRESAHA.109.213256 |
| Citation | Seeger TS, et al. (2010) Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo. Circ Res 106(5):880-90 |
| abstractText | 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. |
