Alpha2M/LRP-1 system induces Shc phosphorylation and NFƒÛB activation in macrophage cell lines.

CACERES LC; LORENC VE; SÁNCHEZ MC; CHIABRANDO GA

San Miguel de Tucumán

Congreso; XLV Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB) 2009.; 2009

SAIB

Alpha2-Macroglobulin (a2M) is a broad specific proteinase inhibitor, which is recognized by LDL receptor-related protein (LRP1), an endocytic receptor belonging to the LDL receptor gene family. Previously, we demonstrated that a2M/LRP1 induces intracellular signaling activation characterized by the activation of PKC and MAPK-ERK1/2 and the expression of MMP-9 in macrophage-derived cell lines. In this work, we investigated the molecular intermediates in the regulation of the intracellular signaling activation induced by α2M/LRP1 system in J774 and RAW 264.7 macrophage derived cell line. By Western blot we observed that α2M induces p52-Shc phosphorylation concomitantly with PKC α/β activation. The α2M-induced Shc activation was fully blocked by GÖ-6976, an inhibitor of PKC α/β, and RAP, an antagonist of the α2M binding to LRP1. In addition, we observed that α2M induced IkBα degradation and NFkB p65 nuclear translocation. Both intracellular pathways induced MMP-9 synthesis, which were fully abolished by the presence of PD98059 and BAY, inhibitors of MAPK-ERK1/2 and NFkB, respectively. In conclusion, our data demonstrate that α2M/LRP1 system promotes the intracellular p52-Shc and NFkB activation, which are responsible for the MMP-9 expression in macrophages.