ArticleThe Journal of clinical investigation2023
Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
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- Selenium and selenoproteins in age-related metabolic diseases: mechanistic insights and translational perspectives.Frontiers in nutrition · 2026Review
- Genetic Polymorphism of Zinc Transporter-8 Gene (SLC30A8), Serum Zinc Concentrations, and Proteome Profiles Related to Type 2 Diabetes in Elderly.Journal of clinical medicine · 2025Article
- The role of insulin signaling with FOXO and FOXK transcription factors.Endocrine journal · 2024Review
- Activation of the insulin receptor by insulin-like growth factor 2.Nature communications · 2024Article
- Insulin receptor Arg717 and IGF-1 receptor Arg704 play a key role in ligand binding and in receptor activation.Open biology · 2023Article
- EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.International journal of molecular sciences · 2023Review
- Review
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
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.
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Registered trials
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