Activated alpha(2)-macroglobulin induces cell proliferation and mitogen-activated protein kinase activation by LRP-1 in the J774 macrophage-derived cell line.
The low-density lipoprotein receptor-related protein-1 (LRP-1) is an endocytic receptor of activated forms of the proteinase inhibitor alpha(2)-macroglobulin (alpha(2)M*). It has been proposed that alpha(2)M* and LRP-1 modulate diverse cellular processes, including cell adhesion, proliferation, and migration, which are involved in inflammation and tumor progression. However, relatively little is known about the role of alpha(2)M*/LRP-1 interaction on these processes. In this work, we demonstrate that alpha(2)M* binding to LRP-1 induces cell proliferation and MAPK activation in the J774 macrophage-derived cell line, which were blocked by RAP, an antagonist of LRP-1-binding ligands, and by PD980059, a specific inhibitor for the Mek1-ERK1/2 pathway. In addition, we demonstrate that LPS, a bacterial product that it is known to down-regulate the LRP-1 expression on macrophage, abrogated the signaling activity triggered by alpha(2)M* on LPS-treated J774 cells. These results suggest that alpha(2)M*/LRP-1 interaction constitutes a key role in the macrophage functioning during inflammation and cancer.
Bonacci
Gustavo R
GR
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Departamento de Bioquímica Clínica, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, Ciudad Universitaria (5000) Córdoba, Argentina.
Cáceres
Leandro C
LC
Sánchez
María C
MC
Chiabrando
Gustavo A
GA
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D000511:alpha-Macroglobulins / Q000378:metabolism*
D005419:Flavonoids; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000511:alpha-Macroglobulins; D048049:Extracellular Signal-Regulated MAP Kinases; D048370:MAP Kinase Kinase 2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one