NICKEL IS A SPECIFIC ANTAGONIST FOR THE CATABOLISM OF ACTIVATED ALPHA(2)-MACROGLOBULIN

The multifunctional low density lipoprotein receptor-related protein/a lpha(2)-macroglobulin receptor (LRP) binds and degrades several ligand s involved in protease and lipoprotein metabolism. We previously repor ted that nickel (Ni2+) specifically inhibits the binding of activated alpha(2)-macroglobulin (alpha(2)M) at 4 degrees C to LRP and had no e ffect on the binding of other ligands to the receptor (Hussain et al. (1995) Biochem. 34, 16074-16081). In the current investigation, we hav e examined the effect of Ni2+ on the catabolism of I-125-labeled alpha (2)M receptor-associated protein (RAP) and lactoferrin at physiologic temperatures by fibroblasts. Nickel completely inhibited the degradat ion of alpha(2)M over a wide range concentrations (0.3-2.4 nM); 50% i nhibition for the degradation of 1.2 nM alpha(2)M was observed at 0.5 mM Ni2+. Furthermore, nickel inhibited the binding, internalization a nd degradation of I-125-alpha(2)M in a dose- and time- dependent mann er. In contrast, the degradation of several concentrations of I-125-RA P by fibroblasts was not affected by different amounts of Ni2+ for var ious times. Similarly, Ni2+ did not inhibit the degradation of lactofe rrin either before or after treating the cells with heparitinase to re move cell-surface proteoglycans. The degradation of lactoferrin was, h owever, inhibited by the RAP indicating that lactoferrin degradation w as mediated by the LRP. These data suggest that Ni2+ is aspecific inhi bitor for the degradation of alpha(2)M.