Format

Send to

Choose Destination
Hum Mol Genet. 2018 Sep 1;27(17):3060-3078. doi: 10.1093/hmg/ddy215.

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

Author information

1
Sorbonne Université, UPMC Paris 06, INSERM UMRS974, Center of Research in Myology, F-75013 Paris, France.
2
Institute for Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
3
Sorbonne Université, UPMC Paris 06, INSERM, UMS29 Omique, F-75013 Paris, France.
4
Sorbonne Université, UPMC Paris 06, INSERM, UMS28 Phénotypage du Petit Animal, Paris F-75013, France.
5
Institut Cochin, INSERM U1016-CNRS UMR 8104, Université Paris Descartes-Sorbonne Paris Cité, Paris F-75014, France.
6
Istituto Clinico Humanitas IRCCS, Milan, Italy.
7
Istituto Ricerca Genetica e Biomedica, National Research Council of Italy, Milan 20089, Italy.
8
Faculté de Médecine La Timone, Université Aix-Marseille, INSERM UMR910, Marseille 13005, France.
9
Department of Physics, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
10
Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
11
Department of Medicine.
12
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

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.

PMID:
29878125
PMCID:
PMC6097156
[Available on 2019-09-01]
DOI:
10.1093/hmg/ddy215

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center