Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
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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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).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Araki et al., 1994
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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
- Update notices
- correction (1994-12-15)
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- 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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