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

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 4

Integrated map showing differential signaling networks stimulated by the ligand-activated WT-IR versus L973F-IR preadipocytes.

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Integrated map showing differential signaling networks stimulated by the...
(A) Quantification of some important phosphosites upregulated by ligand (insulin or IGF-1) for fold-change WT-IR > L973F-IR. (B) Quantification of phosphosite examples upregulated by ligand (insulin or IGF-1) for fold-change L973F-IR > WT-IR. (C) Quantification of phosphosite examples downregulated by ligand (insulin or IGF-1) for fold-change L973-IR > WT-IR. (D) Quantification of phosphosite examples downregulated by ligand (insulin or IGF-1) for fold-change WT > L973F-IR. (E) Quantification of phosphosite examples shown opposite regulation by ligand between WT-IR and L973F-IR. Data are represented as mean ± SEM of phosphosites intensity values. #P < 0.05; ##P < 0.01; ###P < 0.001 versus basal. *P < 0.05; **P < 0.01; ***P < 0.001, WT-IR versus L973F-IR, 2-way ANOVA. (F) Signaling map showing phosphosites unequally up- or downregulated by ligand stimulation of WT-IR and L973F-IR as identified by phosphoproteomics (P < 0.05). Sites with orange only on the left represent sites for which phosphorylation was upregulated more in WT-IR cells than L973F-IR cells following ligand stimulation. Sites with orange only on the right represent sites for which phosphorylation was upregulated more in L973F-IR cells than WT-IR cells following ligand stimulation. Sites with blue only on the left represent sites for which phosphorylation was downregulated more in WT-IR cells than L973F-IR cells following ligand stimulation. Sites with blue only on the right represent sites for which phosphorylation was downregulated more in L973F-IR cells than WT-IR cells following ligand stimulation. Arrows indicate known protein-protein interactions and phosphorylation/dephosphorylation events from databases (PhosphositePlus) and the literature.