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Mutation of Tyrosine Residues 1162 and 1163 of the Insulin Receptor Affects Hormone and Receptor Internalization

Laboratoire de Biochimie et Biologie Cellulaire, INSERM U.181, Faculté de Médecine Saint-Antoine 75571 Paris Cedex 12, France
INSERM U.36 75005 Paris, France

Address requests for reprints to: Dr. Jacqueline Capeau, Laboratoire de Biochimie et Biologie Cellulaire, INSERM U.181, Faculté de Medecine Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12, France.

Abstract

Insulin internalization and degradation, insulin receptor internalization and recycling, as well as long term receptor down-regulation were comparatively studied in Chinese hamster ovary (CHO) cell lines, either parental or expressing the wild-type human insulin receptor (CHO.R) or a mutated receptor in which the tyrosine residues in positions 1162 and 1163 were replaced by phenylalanines (CHO.Y2). The two transfected cell lines presented very similar binding characteristics, and their pulse labeling with [³⁵S]methionine revealed that the receptors were processed normally. As expected, the mutation of these twin tyrosines resulted in a defective insulin stimulation of both receptor kinase activity and glycogen synthesis. We now present evidence that compared to CHO.R cells, which efficiently internalized and degraded insulin, CHO.Y2 cells exhibited a marked defect in hormone internalization, leading to impaired insulin degradation. Moreover, the mutated receptors were found to be less effective than the wild-type receptors in transducing the hormone signal for receptor internalization, whereas the process of receptor recycling after internalization seemed not to be altered. In parental CHO cells, insulin induced long term receptor down-regulation, but was totally ineffective in both transfected cell lines. These results reveal that the tyrosines 1162 and 1163 in the kinase regulatory domain of the receptor β-subunit play a pivotal role in insulin and receptor internalization.

FOOTNOTES

This work was supported by INSERM and the University of Paris VI.

Received for publication August 28, 1989. Revision received November 6, 1989. Accepted for publication November 14, 1989.

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