Altered interaction of Cis-dichlorodiammineplatinum(II)--modified alpha 2-macroglobulin (alpha 2M) with the low density lipoprotein receptor-related protein/alpha 2M receptor but not the alpha 2M signaling receptor.
Receptor-recognized forms of alpha 2-macroglobulin (alpha 2M*) bind to two macrophage receptors: an endocytic receptor, the low density lipoprotein receptor-related protein/alpha 2M receptor (LRP/alpha 2MR), and a G protein-coupled receptor, the alpha 2M signaling receptor (alpha 2MSR). Binding of alpha 2M* to LRP/alpha 2MR but not alpha 2MSR is inhibited by receptor-associated protein. We now present binding characteristics of alpha 2MSR (kD approximately 50 pm; 1,530 sites/cell) using Scatchard analysis. We also demonstrate that chemical modification of alpha 2M* with cis-dichlorodiammineplatinum (cis-DDP) does not significantly alter binding to either receptor or signaling characteristics as compared with unmodified alpha 2M*. However, internalization by LRP/alpha 2MR is greatly affected. Cis-DDP-modified alpha 2M* (cis-DDP-alpha 2M*) and alpha 2M* show comparable internalization during a single round of endocytosis; however, cis-DDP modification of alpha 2M* results in a > or = 82% reduction in internalization involving receptor recycling and multiple rounds of endocytosis. Results from pH 5.0 dissociation and receptor recycling experiments suggest that the mechanism of decreased internalization of cis-DDP-alpha 2M* involves poor dissociation from the receptor in endosomes and a decrease in available surface receptors over the time of exposure to the ligand.
Howard
G C
GC
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Misra
U K
UK
DeCamp
D L
DL
Pizzo
S V
SV
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004705:Endocytosis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011971:Receptors, Immunologic / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000970:Antineoplastic Agents; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D002945:Cisplatin; D002118:Calcium