Association of RhoGEF Ect2 with Desmoplakin Supports RhoA Activity at Intercellular Junctions: Implications for Carvajal Disease

Abstract

Desmoplakin (DP) is an essential component of the desmosomal adhesion complex, tethering intermediate filaments to sites of intercellular adhesion to confer mechanical integrity to tissues. As a frequent target for mutation in cardiocutaneous syndromes that vary widely in phenotype, DPs roles as a signaling hub are rapidly emerging. Here, we identify the RhoGEF Ect2 as a previously unappreciated binding partner of the desmosomal protein DP. DP is required for the localization of Ect2 to keratinocyte desmosomes and cardiac intercalated discs in vitro and in vivo, where it maintains active RhoA (Rho-GTP) at the membrane. We demonstrate further that Ect2 activity is supported by PKC in a DP-dependent manner in cardiac myocytes. Finally, a truncated form of DP expressed in patients with Carvajal syndrome associated with severe cardiocutaneous defects is impaired in its ability to bind and localize Ect2 to cell junctions in cardiomyocytes and keratinocytes isolated from patients. Our findings delineate an important relationship between a component of the desmosome and a critical regulator of actin cytoskeletal remodeling that could have widespread implications for understanding cardiac and cutaneous health and disease pathogenesis.