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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. / Nagao, Hirofumi; Cai, Weikang; Brandão, Bruna B.; Wewer Albrechtsen, Nicolai J.; Steger, Martin; Gattu, Arijeet K.; Pan, Hui; Dreyfuss, Jonathan M.; Thomas Wunderlich, F.; Mann, Matthias; Ronald Kahn, C.

In: Journal of Clinical Investigation, Vol. 133, No. 4, e161472, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Nagao, H, Cai, W, Brandão, BB, Wewer Albrechtsen, NJ, Steger, M, Gattu, AK, Pan, H, Dreyfuss, JM, Thomas Wunderlich, F, Mann, M & Ronald Kahn, C 2023, 'Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling', Journal of Clinical Investigation, vol. 133, no. 4, e161472. https://doi.org/10.1172/JCI161472

APA

Nagao, H., Cai, W., Brandão, B. B., Wewer Albrechtsen, N. J., Steger, M., Gattu, A. K., Pan, H., Dreyfuss, J. M., Thomas Wunderlich, F., Mann, M., & Ronald Kahn, C. (2023). Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. Journal of Clinical Investigation, 133(4), [e161472]. https://doi.org/10.1172/JCI161472

Vancouver

Nagao H, Cai W, Brandão BB, Wewer Albrechtsen NJ, Steger M, Gattu AK et al. Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. Journal of Clinical Investigation. 2023;133(4). e161472. https://doi.org/10.1172/JCI161472

Author

Nagao, Hirofumi ; Cai, Weikang ; Brandão, Bruna B. ; Wewer Albrechtsen, Nicolai J. ; Steger, Martin ; Gattu, Arijeet K. ; Pan, Hui ; Dreyfuss, Jonathan M. ; Thomas Wunderlich, F. ; Mann, Matthias ; Ronald Kahn, C. / Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. In: Journal of Clinical Investigation. 2023 ; Vol. 133, No. 4.

Bibtex

@article{8ac44208735348709198e5f454314be2,
title = "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.",
author = "Hirofumi Nagao and Weikang Cai and Brand{\~a}o, {Bruna B.} and {Wewer Albrechtsen}, {Nicolai J.} and Martin Steger and Gattu, {Arijeet K.} and Hui Pan and Dreyfuss, {Jonathan M.} and {Thomas Wunderlich}, F. and Matthias Mann and {Ronald Kahn}, C.",
note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Nagao et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",
year = "2023",
doi = "10.1172/JCI161472",
language = "English",
volume = "133",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "4",

}

RIS

TY - JOUR

T1 - Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling

AU - Nagao, Hirofumi

AU - Cai, Weikang

AU - Brandão, Bruna B.

AU - Wewer Albrechtsen, Nicolai J.

AU - Steger, Martin

AU - Gattu, Arijeet K.

AU - Pan, Hui

AU - Dreyfuss, Jonathan M.

AU - Thomas Wunderlich, F.

AU - Mann, Matthias

AU - Ronald Kahn, C.

N1 - 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.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1172/JCI161472

DO - 10.1172/JCI161472

M3 - Journal article

C2 - 36548088

AN - SCOPUS:85148114371

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

M1 - e161472

ER -

ID: 339139176