Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation. (5th June 2018)

• Record Type: Journal Article
• Authors: Chatzifrangkeskou, Maria; Yadin, David; Marais, Thibaut; Chardonnet, Solenne; Cohen-Tannoudji, Mathilde; Mougenot, Nathalie; Schmitt, Alain; Crasto, Silvia; Di Pasquale, Elisa; Macquart, Coline; Tanguy, Yannick; Jebeniani, Imen; Pucéat, Michel; Morales Rodriguez, Blanca; Goldmann, Wolfgang H; Dal Ferro, Matteo; Biferi, Maria-Grazia; Knaus, Petra; Bonne, Gisèle; Worman, Howard J; Muchir, Antoine
• Is Part Of: Human molecular genetics. Volume 27:Number 17(2018:Sep. 01)
• Page Start: 3060
• Page End: 3078
• Publication Date: 2018-06-05
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddy215
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: Hyper-activation of extracellular signal-regulated kinase (ERK) 1/2 contributes to heart dysfunction in cardiomyopathy caused by mutations in the lamin A/C gene ( LMNA cardiomyopathy). The mechanism of how this affects cardiac function is unknown. We show that active phosphorylated ERK1/2 directly binds to and catalyzes the phosphorylation of the actin depolymerizing factor cofilin-1 on Thr25. Cofilin-1 becomes active and disassembles actin filaments in a large array of cellular and animal models of LMNA cardiomyopathy. In vivo expression of cofilin-1, phosphorylated on Thr25 by endogenous ERK1/2 signaling, leads to alterations in left ventricular function and cardiac actin. These results demonstrate a novel role for cofilin-1 on actin dynamics in cardiac muscle and provide a rationale on how increased ERK1/2 signaling leads to LMNA cardiomyopathy.