Document Detail

The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein.
MedLine Citation:
PMID:  18987193     Owner:  NLM     Status:  MEDLINE    
Low-density lipoprotein receptor-related protein (LRP-1) is an endocytic receptor for diverse proteins, including matrix metalloproteinase-9 (MMP-9), and a cell-signaling receptor. In the peripheral nervous system (PNS), LRP-1 is robustly expressed by Schwann cells only after injury. Herein, we demonstrate that MMP-9 activates extracellular-signal-regulated kinase (ERK1/2) and Akt in Schwann cells in culture. MMP-9 also promotes Schwann cell migration. These activities require LRP-1. MMP-9-induced cell signaling and migration were blocked by inhibiting MMP-9-binding to LRP-1 with receptor-associated protein (RAP) or by LRP-1 gene silencing. The effects of MMP-9 on Schwann cell migration also were inhibited by blocking the cell-signaling response. An antibody targeting the hemopexin domain of MMP-9, which mediates the interaction with LRP-1, blocked MMP-9-induced cell signaling and migration. Furthermore, a novel glutathione-S-transferase fusion protein (MMP-9-PEX), which includes only the hemopexin domain of MMP-9, replicated the activities of intact MMP-9, activating Schwann cell signaling and migration by an LRP-1-dependent pathway. Constitutively active MEK1 promoted Schwann cell migration; in these cells, MMP-9-PEX had no further effect, indicating that ERK1/2 activation is sufficient to explain the effects of MMP-9-PEX on Schwann cell migration. Injection of MMP-9-PEX into sciatic nerves, 24 h after crush injury, robustly increased phosphorylation of ERK1/2 and Akt. This response was inhibited by RAP. MMP-9-PEX failed to activate cell signaling in uninjured nerves, consistent with the observation that Schwann cells express LRP-1 at significant levels only after nerve injury. These results establish LRP-1 as a cell-signaling receptor for MMP-9, which may be significant in regulating Schwann cell migration and physiology in PNS injury.
Elisabetta Mantuano; Gen Inoue; Xiaoqing Li; Kazuhisa Takahashi; Alban Gaultier; Steven L Gonias; W Marie Campana
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  28     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-06     Completed Date:  2008-12-31     Revised Date:  2013-12-27    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11571-82     Citation Subset:  IM    
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MeSH Terms
Animals, Newborn
Cell Death / drug effects
Cell Movement / drug effects*,  physiology
Cells, Cultured
Drug Interactions
Enzyme Inhibitors / pharmacology
Gene Expression Regulation / drug effects,  physiology
Hemopexin / metabolism*
LDL-Receptor Related Protein-Associated Protein / physiology*
Matrix Metalloproteinase 9 / metabolism,  pharmacology*
Mitogen-Activated Protein Kinase 3 / metabolism
Neuregulin-1 / pharmacology
Oncogene Protein v-akt / metabolism
Protein Interaction Domains and Motifs / drug effects,  physiology
RNA, Small Interfering / pharmacology
Schwann Cells / cytology*,  physiology*
Sciatic Nerve / cytology
Sciatic Neuropathy / metabolism
Signal Transduction / drug effects*,  physiology
rap GTP-Binding Proteins / pharmacology
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/LDL-Receptor Related Protein-Associated Protein; 0/Neuregulin-1; 0/RNA, Small Interfering; 9013-71-2/Hemopexin; EC Protein v-akt; EC Protein Kinase 3; EC Metalloproteinase 9; EC GTP-Binding Proteins

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