Evidence that LDL receptor-related protein 1 acts as an early injury detection receptor and activates c-Jun in Schwann cells.
Schwann cells (SCs) detect injury to peripheral nerves and transform phenotypically to respond to injury and facilitate repair. Cell-signaling pathways and changes in gene expression that drive SC phenotypic transformation in injury have been described; however, the SC receptors that detect peripheral nervous system (PNS) injury have not been identified. LDL receptor-related protein 1 (LRP1) is a receptor for numerous ligands, including intracellular proteins released by injured cells and protein components of degenerated myelin. In certain cell types, including SCs, LRP1 is a cell-signaling receptor. Here, we show that binding of the LRP1 ligand, tissue-type plasminogen activator (tPA), to cultured rat SCs induces c-Jun phosphorylation, a central event in activation of the SC repair program. The response to tPA was blocked by the LRP1 antagonist, receptor-associated protein. c-Jun phosphorylation was also observed when cultured rat SCs were treated with a recombinant derivative of matrix metalloproteinase-9 that contains the LRP1 recognition motif (PEX). The ability of LRP1 to induce c-Jun phosphorylation and ERK1/2 activation was confirmed using cultures of human SCs. When tPA or PEX was injected directly into crush-injured rat sciatic nerves, c-Jun phosphorylation and ERK1/2 activation were observed in SCs in vivo. The ability of LRP1 to bind proteins released in the earliest stages of PNS injury and to induce c-Jun phosphorylation support a model in which SC LRP1 functions as an injury-detection receptor in the PNS.
Department of Anesthesiology
Andreas
A
Flütsch
Department of Anesthesiology
Kenneth
K
Henry
Department of Pathology|Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
Elisabetta
E
Mantuano
Department of Pathology
Michael S
MS
Lam
Department of Anesthesiology|Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
Masataka
M
Shibayama
Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
Kazuhisa
K
Takahashi
Department of Pathology
Steven L
SL
Gonias
Department of Anesthesiology|The Program in Neuroscience, University of California, San Diego, La Jolla, California, USA
Wendy M
WM
Campana
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D026563:LDL-Receptor Related Protein-Associated Protein / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000494:pharmacology; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000166:cytology; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D010959:Tissue Plasminogen Activator
D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016755:Proto-Oncogene Proteins c-jun; D010959:Tissue Plasminogen Activator; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; D020780:Matrix Metalloproteinase 9