Cited by 1,252Metabolism, Diabetes, and CancerGrowth Hormone and Insulin-like Growth FactorsPI3K/AKT/mTOR signaling in cancer

Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene

Araki, Eiichi, Lipes, Myra A., Patti, Mary-Elizabeth, Brüning, Jens Claus, Haag III, Burritt, Johnson, Randall S., Kahn, C. Ronald·1994·Nature

Abstract

The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3'-OH kinase (PI(3)K) and several other proteins containing SH2 (Src-homology 2) domains. To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. These mice had no IRS-1 and showed no evidence of IRS-1 phosphorylation or IRS-1-associated PI(3)K activity. They also had a 50 per cent reduction in intrauterine growth, impaired glucose tolerance, and a decrease in insulin/IGF-1-stimulated glucose uptake in vivo and in vitro. The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.

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Crossref · 10.1038/372186a0

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  • Physiologically, IRS-1 is phosphorylated at tyrosine residues by the tyrosine kinase activity of the insulin receptor, which activates downstream signaling in the insulin pathway.

    “Physiologically, IRS-1 is phosphorylated at tyrosine residues by the tyrosine kinase activity of the IR, which activates downstream signaling in the insulin pathway (Araki et al., 1994; White, 2003).”

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Authors
Araki, E., Lipes, M. A., Patti, M.-E., Brüning, J. C., Haag III, B., Johnson, R. S., & Kahn, C. R.
Affiliations
Joslin Diabetes Center (US)
Venue
Nature
Published
1994-11
Volume
372
Issue
6502
Pages
186-190
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2033429522
Cited by
1,252
References
30
Citations by year
2026: 5 · 2025: 11 · 2024: 12 · 2023: 12 · 2022: 14 · 2021: 18 · 2020: 24 · 2019: 18 · 2018: 31 · 2017: 27 · 2016: 26 · 2015: 29 · 2014: 37 · 2013: 38 · 2012: 35
FWCI
19.77
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
insulin signaling, IRS-1, insulin-like growth factor I, phosphatidylinositol 3-kinase, insulin receptor substrate 2, tyrosine phosphorylation, glucose uptake, glucose tolerance, fetal growth, SH2 domain proteins
MeSH terms
Animals, Blood Glucose, Female, Growth, Insulin, Insulin Resistance, Insulin-Like Growth Factor I, Male, Mice, Inbred C57BL, Phosphoproteins, Tyrosine, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Mice, Knockout, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Mice, Insulin Receptor Substrate Proteins

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