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 GST-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.

LDL receptor-related protein-1 (LRP1) is an endocytic and cellsignaling receptor. In mice in which LRP1 is deleted in myeloid cells, the response to lipopolysaccharide (LPS) was greatly exacerbated. LRP1 deletion in macrophages in vitro, under the control of tamoxifen-activated Cre-ER T fusion protein, robustly increased expression of proinflammatory cytokines and chemokines. In LRP1-expressing macrophages, proinflammatory mediator expression was regulated by LRP1 ligands in a ligand-specific manner. The LRP1 agonists, α 2 -macroglobulin and tissue-type plasminogen activator, attenuated expression of inflammatory mediators, even in the presence of LPS. The antagonists, receptor-associated protein (RAP) and lactoferrin (LF), and LRP1-specific antibody had the entirely opposite effect, promoting inflammatory mediator expression and mimicking LRP1 deletion. NFκB was rapidly activated in response to RAP and LF and responsible for the initial increase in expression of proinflammatory mediators. RAP and LF also significantly increased expression of microRNA-155 (miR-155) after a lag phase of about 4 h. miR-155 expression reflected, at least in part, activation of secondary cell-signaling pathways downstream of TNFα. Although miR-155 was not involved in the initial induction of cytokine expression in response to LRP1 antagonists, miR-155 was essential for sustaining the proinflammatory response. We conclude that LRP1, NFκB, and miR-155 function as members of a previously unidentified system that has the potential to inhibit or sustain inflammation, depending on the continuum of LRP1 ligands present in the macrophage microenvironment.LDL receptor-related protein-1 | tissue-type plasminogen activator | lipopolysaccharide | NFκB | microRNA-155

Low-density lipoprotein receptor-related protein 1 (LRP1) functions in endocytosis and intracellular signaling for a variety of structurally diverse ligands. Although LRP1 has been implicated in several aspects of neuronal function, molecular mechanisms underlying the activity of neuronal LRP1 remain unclear. Here, we describe a signaling pathway whereby LRP1 transactivates Trk receptors. Binding of tissue-type plasminogen activator or α2-macroglobulin (α2M) to LRP1 resulted in Src family kinase (SFK) activation and SFK-dependent Trk receptor transactivation in PC12 cells and neurons. Trk receptor transactivation was necessary for activation of Akt and extracellular signal-regulated kinase, and for neurite outgrowth downstream of LRP1. Injection of the LRP1-binding domain of α2M into rat dorsal root ganglia induced Trk receptor phosphorylation, which was blocked by receptor-associated protein, an antagonist of ligand binding to LRP1. Trk receptor transactivation provides a mechanism by which diverse LRP1 ligands may demonstrate neurotrophic activity.

Background: LRP1 is a cell signaling receptor in neurons. Results: LRP1, NMDA receptor, and Trk compose a single system, activating cell signaling in response to tPA and ␣ 2 -macroglobulin. MAG binding to LRP1 recruits p75NTR but not Trk. Conclusion: Ligand-specific co-receptor recruitment explains how LRP1 activates distinct cell signaling pathways in response to different ligands. Significance: Distinct co-receptor assemblies allow LRP1 to regulate the cellular response to its microenvironment.