LRP-1 is a LDL receptor gene family member synthesized and
processed into 515-kDa extracelullar á chain and 85-kDa transmembrane
and intracelullar â chain. LRP-1 á chain contains
multiple ligand recognition sites and â chain harbors motifs for
endocytosis and signaling. In addition to á2-macroglobulinprotease
complexes (á2M*), LRP-1 also recognizes proteases
and lactoferrin. The receptor-associated protein (RAP) inhibits
the binding of LRP-1 ligands. Previously, we have demonstrated
that á2M* promotes cell proliferation and intracelullar calcium in
J774 cells by LRP-1, but the signaling mechanisms are unknown
yet. Herein we evaluate the signaling effects of á2M* and other
LRP-1 ligands. By Western blot we observed that á2M* 60 nM
promoted MAPK-ERK1/2 phosphorilation, whereas RAP and
lactoferrin did not induce it. The á2M*-induced ERK1-2-MAPK
phosphorilation was inhibited by MEK-1 PD98059 inhibitor and
RAP. When the J774 cells were cultured with Ca2+ antagonist
BAPTA and the PKC Calphostin C inhibitor, the á2M*-induced
ERK1-2-MAPK phosphorilation was blocked. In conclusion, á2M*
induces ERK1-2-MAPK activation by intracellular calcium rises
and PKC activation mediated by LRP-1 in J774 cells. Other LRP-
1 ligands did not induce intracellular signal. Thus, the ligand
recognition in the LRP-1 á chain might regulate and activate
different downstream signaling pathways.
