title: Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.
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.
authors.affiliation: From the Department of Internal Medicine.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Bullard
authors.affiliation: Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Seo
authors.affiliation: the Buck Institute for Research on Aging, Novato, California 94945, and.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schilling
authors.affiliation: From the Department of Internal Medicine.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.|Emmyon, Inc., Coralville, Iowa 52241.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Dyle
authors.affiliation: From the Department of Internal Medicine.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dierdorff
authors.affiliation: From the Department of Internal Medicine.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.|Emmyon, Inc., Coralville, Iowa 52241.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Ebert
authors.affiliation: From the Department of Internal Medicine.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.
authors.forename: Austin D
authors.initials: AD
authors.lastname: DeLau
authors.affiliation: the Buck Institute for Research on Aging, Novato, California 94945, and.|the Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143.
authors.forename: Bradford W
authors.initials: BW
authors.lastname: Gibson
authors.affiliation: From the Department of Internal Medicine, christopher-adams@uiowa.edu.|Fraternal Order of Eagles Diabetes Research Center, and.|Departments of Molecular Physiology and Biophysics and.|the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa 52246.|Emmyon, Inc., Coralville, Iowa 52241.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D048768:MAP Kinase Kinase Kinase 4; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C482780:Map3k4 protein, mouse
keywords: Gadd45a; MEKK4; aging; mass spectrometry (MS); muscle; muscle atrophy; skeletal muscle; skeletal muscle metabolism