Endocytosis, recycling, and degradation of the insulin receptor. Studies with monoclonal antireceptor antibodies that do not activate receptor kinase.
The endocytosis, recycling, and degradation of the insulin receptor were studied in IM-9 cells and U-937 cells by employing two monoclonal antibodies directed at the alpha subunit of the human insulin receptor, antibodies MA-5 and MA-10. Antibody MA-5 is an insulin agonist and MA-10 is an insulin antagonist (Forsayeth, J., Caro, J.F., Sinha, M.K., Maddux, B.A., and Goldfine, I.D. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 3448-3451). Both monoclonal antibodies, like insulin, induced the endocytosis of the insulin receptor within 15 min. Upon removal of extracellular ligand the internalized receptor recycled to the cell surface. At this time there was no degradation of the receptor as measured by a sensitive insulin receptor radioimmunoassay. After 20 h of incubation, insulin and MA-5, but not MA-10, induced significant receptor degradation as measured by both insulin receptor radioimmunoassay and metabolic labeling studies. These studies demonstrated, therefore, that: 1) internalization and recycling of the receptor can be induced by antireceptor monoclonal antibodies that are either insulin agonists or insulin antagonists; 2) enhanced receptor degradation can be induced by monoclonal antibodies that are insulin agonists; and 3) the process of receptor internalization does not necessarily lead to enhanced receptor degradation. Since prior studies have indicated that neither MA-5 nor MA-10 enhance insulin receptor kinase activity, the present studies also suggest that insulin receptor endocytosis and degradation induced by ligands different than insulin can occur without activation of this process.
Trischitta
V
V
Cattedra di Endocrinologi dell' Universita' di Catania, Italy.
Wong
K Y
KY
Brunetti
A
A
Scalisi
R
R
Vigneri
R
R
Goldfine
I D
ID
D000911:Antibodies, Monoclonal / Q000145:classification / Q000502:physiology*; D002460:Cell Line; D004705:Endocytosis; D004789:Enzyme Activation; D000939:Epitopes / Q000276:immunology; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin