title: 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.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Pathology, University of California, San Diego, La Jolla, California 92093-0629, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.forename: Gen
authors.initials: G
authors.lastname: Inoue
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: W Marie
authors.initials: WM
authors.lastname: Campana
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006466:Hemopexin / Q000378:metabolism*; D026563:LDL-Receptor Related Protein-Associated Protein / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012583:Schwann Cells / Q000166:cytology* / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology; D020426:Sciatic Neuropathy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020668:rap GTP-Binding Proteins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D026563:LDL-Receptor Related Protein-Associated Protein; D020890:Neuregulin-1; D034741:RNA, Small Interfering; D006466:Hemopexin; D051058:Oncogene Protein v-akt; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D020668:rap GTP-Binding Proteins