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Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling
Hirofumi Nagao, … , Matthias Mann, C. Ronald Kahn
Hirofumi Nagao, … , Matthias Mann, C. Ronald Kahn
Published December 22, 2022
Citation Information: J Clin Invest. 2023;133(4):e161472. https://doi.org/10.1172/JCI161472.
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Research Article Endocrinology Metabolism Article has an altmetric score of 7

Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling

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Abstract

Insulin and IGF-1 receptors (IR and IGF1R) are highly homologous and share similar signaling systems, but each has a unique physiological role, with IR primarily regulating metabolic homeostasis and IGF1R regulating mitogenic control and growth. Here, we show that replacement of a single amino acid at position 973, just distal to the NPEY motif in the intracellular juxtamembrane region, from leucine, which is highly conserved in IRs, to phenylalanine, the highly conserved homologous residue in IGF1Rs, resulted in decreased IRS-1/PI3K/Akt/mTORC1 signaling and increased Shc/Gab1/MAPK cell cycle signaling. As a result, cells expressing L973F-IR exhibited decreased insulin-induced glucose uptake, increased cell growth, and impaired receptor internalization. Mice with knockin of the L973F-IR showed similar alterations in signaling in vivo, and this led to decreased insulin sensitivity, a modest increase in growth, and decreased weight gain when mice were challenged with a high-fat diet. Thus, leucine-973 in the juxtamembrane region of the IR acts as a crucial residue differentiating IR signaling from IGF1R signaling.

Authors

Hirofumi Nagao, Weikang Cai, Bruna B. Brandão, Nicolai J. Wewer Albrechtsen, Martin Steger, Arijeet K. Gattu, Hui Pan, Jonathan M. Dreyfuss, F. Thomas Wunderlich, Matthias Mann, C. Ronald Kahn

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Figure 5

Effects of L973F substitution in IR on gene transcription.

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Effects of L973F substitution in IR on gene transcription.
(A) Relative ...
(A) Relative mRNA expression of P53 and P21 in WT-IR and L973F-IR cells. WT-IR and L973F-IR preadipocytes were stimulated with or without 100 nM insulin for 6 hours after 6 hours of FBS starvation. Gene expression levels of WT-IR cells at the basal were set at 1. (B) Fold changes of P53 and P21 expression in response to insulin stimulation in WT-IR and L973F-IR cells. (C) Gene expression levels of Ccl2 in response to insulin stimulation in WT-IR and L973F-IR cells. (D) Gene expression levels of Il6 in response to insulin stimulation in WT-IR and L973F-IR cells. (E and F) Fold changes of expression in response to insulin stimulation for genes associated with fatty acid synthesis (E) and cholesterol biosynthesis (F) in WT-IR and L973F-IR cells. Data are represented as mean ± SEM. #P < 0.05; ##P < 0.01; ###P < 0.001, basal versus ligand. *P < 0.05; **P < 0.01, WT-IR versus L973F-IR, Student’s t test for fold change analysis and 2-way ANOVA for others.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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