Nickel is a specific antagonist for the catabolism of activated alpha 2-macroglobulin.
The multifunctional low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) binds and degrades several ligands involved in protease and lipoprotein metabolism. We previously reported that nickel (Ni2+) specifically inhibits the binding of activated alpha 2-macroglobulin (alpha 2 M*) at 4 degrees C to LRP and had no effect on the binding of other ligands to the receptor (Hussain et al. (1995) Biochem. 34, 16074-16081). In the current investigation, we have examined the effect of Ni2+ on the catabolism of 125 I-labeled alpha 2M*, receptor-associated protein (RAP) and lactoferrin at physiologic temperatures by fibroblasts. Nickel completely inhibited the degradation of alpha 2M* over a wide range of concentrations (0.3-2.4 nM); 50% inhibition for the degradation of 1.2 nM alpha 2M* was observed at 0.5 mM Ni2+. Furthermore, nickel inhibited the binding, internalization and degradation of 125I-alpha 2M* in a dose- and time-dependent manner. In contrast, the degradation of several concentrations of 125I-RAP by fibroblasts was not affected by different amounts of Ni2+ for various times. Similarly, Ni2+ did not inhibit the degradation of lactoferrin either before or after treating the cells with heparitinase to remove cell-surface proteoglycans. The degradation of lactoferrin was, however, inhibited by the RAP indicating that lactoferrin degradation was mediated by the LRP. These data suggest that Ni2+ is a specific inhibitor for the degradation of alpha 2M*.
Kancha
R K
RK
Department of Pathology, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.
Hussain
M M
MM
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts; D006023:Glycoproteins / Q000378:metabolism*; D007457:Iodine Radioisotopes; D026563:LDL-Receptor Related Protein-Associated Protein; D007781:Lactoferrin / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D009532:Nickel / Q000494:pharmacology*; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism*
D002352:Carrier Proteins; D006023:Glycoproteins; D007457:Iodine Radioisotopes; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D009532:Nickel; D007781:Lactoferrin; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase