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J. Biol. Chem., Vol. 266, Issue 34, 23068-23073, 12, 1991
M Rajagopalan, JL Neidigh and DA McClain
We have recently shown that the immediately submembranous domain of the
human insulin receptor (hIR) is required for rapid ligand-dependent
internalization (Thies, R. S., Webster, N. J., and McClain, D. A. (1990) J.
Biol. Chem. 265, 10132-10137). This region contains one copy of an NPXY
sequence that is required for endocytosis of the low density lipoprotein
receptor. In order to dissect and analyze the specific sequences involved
in endocytosis of the insulin receptor, we have mutated the NPXY sequence
from NPEY (residues 957-960) to APEA (NPEY/APEA). In addition, we have
mutated a similar sequence in the same region, changing GPLY (residues
950-953) to APLA (GPLY/APLA). The cDNAs encoding the normal hIR and these
mutant receptors were transfected into Rat 1 fibroblasts. The expressed
receptors bound insulin with high affinity and retained insulin-stimulated
tyrosine kinase activity. Despite the ability of these mutant receptors to
bind insulin and undergo autophosphorylation, the GPLY/APLA receptor
internalized insulin at only 32% of the rate of normal hIR at low receptor
occupancy. On the other hand, the NPEY/APEA receptor internalized insulin
at 87% of the normal rate. These results were confirmed by measuring
internalization of photoaffinity-labeled insulin receptors. Another
receptor with both the NPEY/APEA and GPLY/APLA mutations internalized to a
lesser degree than the GPLY/APLA receptor and at a rate equivalent to that
seen for a receptor with the entire submembranous domain deleted. A
receptor with the complete normal submembranous domain but with the
tyrosine kinase and C-terminal region of the hIR deleted exhibited only a
basal internalization rate. We conclude that the information contained in
the GPLY and, to a lesser extent, the NPEY sequences are necessary but not
sufficient for signaling internalization of the insulin receptor.
Amino acid sequences Gly-Pro-Leu-Tyr and Asn-Pro-Glu-Tyr in the submembranous domain of the insulin receptor are required for normal endocytosis
Veterans Administration Medical Center, Birmingham, Alabama.
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