Logo image
Back
Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4
Journal article   Open access   Peer reviewed

Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4

Steven A Bullard, Seongjin Seo, Birgit Schilling, Michael C Dyle, Jason M Dierdorff, Scott M Ebert, Austin D DeLau, Bradford W Gibson and Christopher M Adams
The Journal of biological chemistry, Vol.291(34), pp.17496-17509
08/19/2016
DOI: 10.1074/jbc.M116.740308
PMCID: PMC5016147
PMID: 27358404
url
https://doi.org/10.1074/jbc.M116.740308View
Published (Version of record) Open Access

Abstract

Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.
 Muscular Atrophy - metabolism Muscular Atrophy - pathology Cell Cycle Proteins - metabolism Multiprotein Complexes - genetics Muscular Atrophy - genetics Nuclear Proteins - metabolism Muscle Fibers, Skeletal - metabolism MAP Kinase Kinase Kinase 4 - genetics Multiprotein Complexes - metabolism Animals Muscle Fibers, Skeletal - pathology Cell Cycle Proteins - genetics Mice MAP Kinase Kinase Kinase 4 - metabolism Nuclear Proteins - genetics

Details

Metrics

26 Record Views
43 Times Cited - Web of Science
Logo image