Activated α₂‐Macroglobulin Induces Mesenchymal Cellular Migration Of Raw264.7 Cells Through Low‐Density Lipoprotein Receptor‐Related Protein 1

Abstract

Distinct modes of cell migration contribute to diverse types of cell movements. The mesenchymal mode is characterized by a multistep cycle of membrane protrusion, the formation of focal adhesion, and the stabilization at the leading edge associated with the degradation of extracellular matrix (ECM) components and with regulated extracellular proteolysis. Both α -Macroglobulin (α M) and its receptor, low density lipoprotein receptor-related protein 1 (LRP1), play important roles in inflammatory processes, by controlling the extracellular activity of several proteases. The binding of the active form of α M (α M*) to LRP1 can also activate different signaling pathways in macrophages, thus inducing extracellular matrix metalloproteinase-9 (MMP-9) activation and cellular proliferation. In the present study, we investigated whether the α M*/LRP1 interaction induces cellular migration of the macrophage-derived cell line, Raw264.7. By using the wound-scratch migration assay and confocal microscopy, we demonstrate that α M* induces LRP1-mediated mesenchymal cellular migration. This migration exhibits the production of enlarged cellular protrusions, MT1-MMP distribution to these leading edge protrusions, actin polymerization, focal adhesion formation, and increased intracellular LRP1/β1-integrin colocalization. Moreover, the presence of calphostin-C blocked the α M*-stimulated cellular protrusions, suggesting that the PKC activation is involved in the cellular motility of Raw264.7 cells. These findings could constitute a therapeutic target for inflammatory processes with deleterious consequences for human health, such as rheumatoid arthritis, atherosclerosis and cancer. J. Cell. Biochem. 118: 1810-1818, 2017. © 2016 Wiley Periodicals, Inc.

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

“…Within the OL lineage, LRP1 is highly expressed by OPCs and is rapidly down-regulated upon differentiation (Cahoy et al, 2008;Zhang et al, 2014;Auderset et al, 2016a;Fernandez-Castaneda et al, 2019), suggesting that LRP1 regulates the function or behavior of the progenitor cells. As LRP1 can signal in a number of different ways (Lillis et al, 2008;Auderset et al, 2016b;Bres and Faissner, 2019) and has been shown to influence cellular behaviors relevant to OPCs, such as proliferation, differentiation (Boucher et al, 2007;Mao et al, 2016;Safina et al, 2016) and migration (Mantuano et al, 2010(Mantuano et al, , 2015Barcelona et al, 2013;Ferrer et al, 2016;Sayre and Kokovay, 2019), we took a conditional gene deletion approach to determine whether Lrp1 influenced the behavior of adult mouse OPCs. We report that Lrp1-deletion produces a delayed increase in adult OPC proliferation and increases the number of OPCs that differentiate into mature, myelinating OLs in the motor cortex and corpus callosum.…”

The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism, Glucose Homeostasis and Inflammation

“…LRP1 binds and internalizes more than 40 unrelated ligands, such as the α2-macroglobulin-protease complex (α2M) and triglyceride-rich lipoprotein-derived apolipoprotein E (apoE), which are mainly degraded by lysosomas [ 4 ]. In addition, the endocytosis and intracellular trafficking of LRP1 plays a key role in regulating the cellular functions and activities of other receptors and plasma membrane proteins that molecularly interact with LRP1, such as platelet-derived growth factor receptor β (PDGFR β) [ 5 ], urokinase-plasminogen activator receptor (uPAR) [ 6 ], membrane type 1-MMP (MT1-MMP) [ 7 ], β1-integrin [ 8 , 9 ], insulin receptor (IR) [ 10 , 11 ], insulin-like growth factor receptor-1 (IGFR-1) [ 12 ] and glucose transporter type 4 (GLUT4) [ 13 ].…”

SAK-HV Promotes RAW264.7 cells Migration Mediated by MCP-1 via JNK and NF-κB Pathways

“…So, we next asked whether SAK-HV facilitated migration by the production of key cytokines. Given the important function of MMPs family in ECM remodeling, we also focused on MMP-9, which have been regarded as a hallmark of mesenchymal migration mode that macrophages adopt38. In SAK-HV-treated cells, MCP-1, MIP-1α as well as MMP-9 were significantly elevated in mRNA levels.…”