Cofilin-1 phosphorylation catalyzed by ERK1/2 alters cardiac actin dynamics in dilated cardiomyopathy caused by lamin A/C gene mutation

Journal article

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.

Authors: Chatzifrangkeskou, M; Yadin, D; Marais, T; Chardonnet, S; Cohen-Tannoudji, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Human Molecular Genetics
• Volume: 27
• Issue: 17
• Pages: 3060-3078
• Publication date: 2018-06-05
• Acceptance date: 2018-05-30
• DOI: 10.1093/hmg/ddy215
• EISSN: 1460-2083
• ISSN: 0964-6906
• Pmid: 29878125
• Language: English
• Keywords: FFR; phosphotransferases; lmna gene; lamin type A; cardiomyopathy; signal transduction; actins; mice; phosphorylation; mutation; cardiomyopathy, dilated; heart