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

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

doi:10.1172/JCI161472

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

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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12 Scopus citations

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.

Original language	English
Article number	e161472
Journal	Journal of Clinical Investigation
Volume	133
Issue number	4
DOIs	https://doi.org/10.1172/JCI161472
State	Published - Feb 15 2023

Bibliographical note

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.

Funding

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.

Funders	Funder number
CECAD Exzellant in Alternsforschung
Center for Molecular Medicine Cologne
Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases
EliteForsk Rejsestipendiat
Endocrinology and Metabolism	NNF19OC0055001
Sunstar Foundation
National Institutes of Health (NIH)	R01DK031036
National Institutes of Health (NIH)
NIDDK Diabetes Research Center
Diabetes Research Connection	P30DK036836
Diabetes Research Connection
Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research	P30 DK057521, K01 DK120740
Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research

ASJC Scopus subject areas

General Medicine

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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.",

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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.

PY - 2023/2/15

Y1 - 2023/2/15

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.

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

Abstract

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