Binding of receptor-recognized forms of α2-macroglobulin to the α2- macroglobulin signaling receptor activates phosphatidylinositol 3-kinase

Abstract

Ligation of the α2-macroglobulin (α2M) signaling receptor by receptor-recognized forms of α2M (α2M*) initiates mitogenesis secondary to increased intracellular Ca2+. We report here that ligation of the α2M signaling receptor also causes a 1.5-2.5-fold increase in wortmannin- sensitive phosphatidylinositol 3-kinase (PI3K) activity as measured by the quantitation of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 formation was α2M* concentration-dependent with a maximal response at ~50 pM ligand concentration. The peak formation of PIP3 occurred at 10 min of incubation. The α2M receptor binding fragment mutant K1370R which binds to the α2M signaling receptor activating the signaling cascade, increased PIPs formation by 2-fold. The mutant K1374A, which binds very poorly to the α2M signaling receptor, did not cause any increase in PIPs formation. α2M* induced DNA synthesis was inhibited by wortmannin. 1,2-Bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acetoxymethylester a chelator of intracellular Ca2+, drastically reduced α2M*-induced increases in PIP3 formation. We conclude that PI3K is involved in α2M*-induced mitogenesis in macrophages and intracellular Ca2+ plays a role in PI3K activation.