Document Detail


MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function.
MedLine Citation:
PMID:  22345520     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Macrophages play critical roles in events ranging from host defense to obesity and cancer, where they infiltrate affected tissues and orchestrate immune responses in tandem with the remodeling of the extracellular matrix (ECM). Despite the dual roles played by macrophages in inflammation, the functions of macrophage-derived proteinases are typically relegated to tissue-invasive or -degradative events. Here we report that the membrane-tethered matrix metalloenzyme MT1-MMP not only serves as an ECM-directed proteinase, but unexpectedly controls inflammatory gene responses wherein MT1-MMP(-/-) macrophages mount exaggerated chemokine and cytokine responses to immune stimuli both in vitro and in vivo. MT1-MMP modulates inflammatory responses in a protease-independent fashion in tandem with its trafficking to the nuclear compartment, where it triggers the expression and activation of a phosphoinositide 3-kinase δ (PI3Kδ)/Akt/GSK3β signaling cascade. In turn, MT1-MMP-dependent PI3Kδ activation regulates the immunoregulatory Mi-2/NuRD nucleosome remodeling complex that is responsible for controlling macrophage immune response. These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses.
Authors:
Ryoko Shimizu-Hirota; Wanfen Xiong; B Timothy Baxter; Steven L Kunkel; Ivan Maillard; Xiao-Wei Chen; Farideh Sabeh; Rui Liu; Xiao-Yan Li; Stephen J Weiss
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Genes & development     Volume:  26     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-20     Completed Date:  2012-04-02     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  395-413     Citation Subset:  IM    
Affiliation:
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Cell Movement
Cell Nucleus / metabolism
Cells, Cultured
Cytokines / genetics
Gene Expression Regulation
Macrophages / cytology,  immunology*,  metabolism
Male
Matrix Metalloproteinase 14 / metabolism*
Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
Mice
Nucleosomes / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Protein Transport
Proteolysis
Grant Support
ID/Acronym/Agency:
CA071699/CA/NCI NIH HHS; CA088308/CA/NCI NIH HHS; P60 DK020572/DK/NIDDK NIH HHS; R01 AI091627/AI/NIAID NIH HHS; R01 CA116516/CA/NCI NIH HHS; R01 HL031237/HL/NHLBI NIH HHS; R01 HL062400/HL/NHLBI NIH HHS; R01 HL089216/HL/NHLBI NIH HHS; R01 HL62400/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Mmp14 protein, mouse; 0/Nucleosomes; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.137/Pik3cd protein, mouse; EC 3.4.24.80/Matrix Metalloproteinase 14; EC 3.5.1.98/Mi-2 Nucleosome Remodeling and Deacetylase Complex
Comments/Corrections
Erratum In:
Genes Dev. 2012 May 15;26(10):1122

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  mtDNA lineage analysis of mouse L-cell lines reveals the accumulation of multiple mtDNA mutants and ...
Next Document:  Model-based Reconstruction Integrated with Fluence Compensation for Photoacoustic Tomography.