Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling
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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.
Originalsprog | Engelsk |
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Artikelnummer | e161472 |
Tidsskrift | Journal of Clinical Investigation |
Vol/bind | 133 |
Udgave nummer | 4 |
Antal sider | 18 |
ISSN | 0021-9738 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by NIH grant R01DK031036 (to CRK) and Joslin Diabetes Research Center (DRC) grant (P30DK036836). HN was supported by a Sunstar Foundation postdoctoral fellowship and a Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowship. WC was supported by NIH grants K01 DK120740 and P30 DK057521. NJWA was supported by an Excellence Emerging Investigator Grant–Endocrinology and Metabolism (NNF19OC0055001) and EliteForsk Rejsestipendiat (2016). FTW received generous funding from Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC). We are grateful for technical assistance by Patrick Jankowski, Cathy Baitzel, Anke Lietzau, and Ingo Voigt.
Publisher Copyright:
Copyright: © 2023, Nagao et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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