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The Journal of Neuroscience, November 5, 2008, 28(45):11571-11582; doi:10.1523/JNEUROSCI.3053-08.2008

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Cellular/Molecular
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

Elisabetta Mantuano,^1,2 Gen Inoue,^1,3 Xiaoqing Li,¹ Kazuhisa Takahashi,³ Alban Gaultier,² Steven L. Gonias,² and W. Marie Campana¹

Departments of ¹Anesthesiology and ²Pathology, University of California, San Diego, La Jolla, California 92093-0629, and ³Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

Correspondence should be addressed to Dr. W. Marie Campana, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, MTF 443, La Jolla, CA 92093-0629. Email: wcampana{at}ucsd.edu

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.

Key words: Schwann cell; peripheral nerve; proteinase; cell migration; hemopexin; phosphatidylinositol 3 kinase; ERK/MAP kinase

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Received July 1, 2008; revised Sept. 17, 2008; accepted Sept. 25, 2008.

Correspondence should be addressed to Dr. W. Marie Campana, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, MTF 443, La Jolla, CA 92093-0629. Email: wcampana{at}ucsd.edu

This article has been cited by other articles:

				Y. Shi, E. Mantuano, G. Inoue, W. M. Campana, and S. L. Gonias Ligand Binding to LRP1 Transactivates Trk Receptors by a Src Family Kinase-Dependent Pathway Sci. Signal., April 28, 2009; 2(68): ra18 - ra18. [Abstract] [Full Text] [PDF]

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