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J Biol Chem, Vol. 273, Issue 34, 22007-22013, August 21, 1998

ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase
THE ROLE OF ENDOSOMAL ACIDIFICATION

Jean-Olivier Contreres, Robert Faure^§, Gerardo Baquiran, John J. Bergeron, and Barry I. Posner

From the  Polypeptide Hormone Laboratory, the  Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada and the ^§ Department de Medecine et le Centre de Recherche du CHUL, Universite Laval, St. Foy, Quebec G1V 4G2, Canada

Incubating endosomes with ATP decreased binding of ¹²⁵I-insulin but not ¹²⁵I-labeled human growth hormone. Increasing ATP concentrations from 0.1 to 1 mM increased -subunit tyrosine phosphorylation and insulin receptor kinase (IRK) activity assayed after partial purification. At higher (5 mM) ATP concentrations -subunit tyrosine phosphorylation and IRK activity were markedly decreased. This was not observed with nonhydrolyzable analogs of ATP, nor with plasma membrane IRK, nor with endosomal epidermal growth factor receptor kinase autophosphorylation. The inhibition of endosomal IRK tyrosine phosphorylation and activity was completely reversed by bafilomycin A₁, indicating a role for endosomal proton pump(s). The inhibition of IRK was not due to serine/threonine phosphorylation nor was it influenced by the inhibition of phosphotyrosyl phosphatase using bisperoxo(1,10-phenanthroline)oxovanadate anion. Prior phosphorylation of the -subunit with 1 mM ATP did not prevent the inhibition of IRK activity on incubating with 5 mM ATP. To evaluate conformational change we incubated endosomes with dithiothreitol (DTT) followed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions. Without DTT the predominant species of IRK observed was _22. With DTT the dimer predominated but on co-incubation with 5 mM ATP the ₂₂ form predominated. Thus, ATP-dependent endosomal acidification contributes to the termination of transmembrane signaling by, among other processes, effecting a deactivating conformational change of the IRK.

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