Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling
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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.
I: Journal of Clinical Investigation, Bind 133, Nr. 4, e161472, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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