EFFECTS OF A2-MACROGLOBULIN (ALPHA2M) ON THE ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS USING CELL LINES WITH DIFFERENTIAL EXPRESSION OF A2M RECEPTORS

CÁCERES LC, BARCELONA PF, CESCHIN DG, BONACCI GR, CHIABRANDO GA.

Mendoza

Congreso; 41st Annual Meeting - XLI Reunión Anual -Argentine Society for Biochemistry and Molecular Biology; 2005

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Alpha 2-M is a broad specific plasma proteinase inhibitor. Upon binding to proteinases, it undergoes a major conformational change that exposes receptor recognition, which is named as (alpha2M*). Two surface cell receptors have been proposed for alpha2M*: LRP-1 and Grp78. Our results and other authors have demonstrated that alpha2M* generate cellular proliferation and activate intracellular signaling pathways such as MAPK and PKB. However, the molecular mechanisms about the alpha2M* receptors involved are unclear. In this work we investigated the surface cell receptor responsible to mediate the intracellular signaling pathways by alpha2M* using cell lines that express constitutively and differentially both alpha2M* receptors. With this propose, we used macrophage derived cell line, J774, which is LRP-1(+) and grp78(-), and the cell line Cho-K1 which is LRP-1(-) and grp78(+). On these cell lines we analyzed the down-stream effect of alpha2M*, measuring ERK-MAPK and JNK-MAPK pathways by Western blotting. The main results obtained showed that alpha2M* at different concentrations (7, 20, 60 and 180 nM) promoted in J774 and Cho-K1 a differential kinetics of ERK1/2 phosphorilation and C-jun activation. In conclusion, we demonstrated that alpha2M* activates intracellular signaling pathways, which are mediated by LRP-1. In addition, this work constitutes the first evidence that LRP-1 can activate the JNK/MAPK pathways.