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

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 8

Effects of L973F substitution on metabolism and growth in mice.

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Effects of L973F substitution on metabolism and growth in mice. (A) BW o...
(A) BW of WT and L973F-IR male mice measured over the indicated time course. All mice were fed a normal chow diet (n = 6–8). (B) Body length of 7-month-old male chow-fed mice (n = 6–8). (C) Tibial length as measured by dual x-ray absorptiometry (DEXA) scan in 21-week-old male chow-fed animals (n = 6–8). (D) IPGTTs were performed at 16 weeks of age in male chow-fed animals (n = 6–8) as described in Methods. (E) ITTs were performed in 14-week-old male chow-fed mice as described in Methods (n = 6). (F) Area over the curve of blood glucose during ITT. (G) BWs of WT and L973F-IR male mice were measured over the indicated time course. These mice were fed an HFD from 8 weeks of age for 3 months (n = 8-10). (H) Tissue weights of 5-month-old HFD-fed male mice (n = 7–12). Epi WAT, epididymal WAT; BAT, brown adipose tissue; Gas muscle, gastrocnemius muscle. (I) Changes in mRNA levels of genes associated with adipogenesis, lipogenesis, and cholesterol synthesis in Sub WAT of WT and L973F-IR HFD–fed male mice (n = 6–9). (J) IPGTT in HFD-fed male mice at 19 weeks of age (n = 7). (K) Area under the curve of blood glucose during IPGTT in HFD-fed male mice. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01, WT versus L973F-IR mice, unpaired Student’s t test.