Journal Article10.1038/372186A0
Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene
E. Araki,E. Araki,Myra A. Lipes,Mary-Elizabeth Patti,Jens C. Brüning,Burritt L. Haag,Randall S. Johnson,C. Ronald Kahn +7 more
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TL;DR: Evidence is provided for IRS- 1-dependent and IRS-1-indepen-dent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.
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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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Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r)
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TL;DR: In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis.
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Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.
Xiao Jian Sun,P. Rothenberg,P. Rothenberg,C R Kahn,Jonathan M. Backer,E. Araki,P. A. Wilden,D. A. Cahill,Barry J. Goldstein,Morris F. White +9 more
TL;DR: During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS–1 acts as a multisite Mocking' protein to bind signal-transducing molecules containing Src-homology 2 and SRC-Homology-3 domains, which may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
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Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.
Hiroyuki Tamemoto,Takashi Kadowaki,Kazuyuki Tobe,Takeshi Yagi,Hiroshi Sakura,Takaki Hayakawa,Takaki Hayakawa,Yasuo Terauchi,Kohjiro Ueki,Yasushi Kaburagi,Shinobu Satoh,Hisahiko Sekihara,Shinji Yoshioka,Hiroyoshi Horikoshi,Yasuhide Furuta,Yoji Ikawa,Masato Kasuga,Yoshio Yazaki,Shinichi Aizawa +18 more
TL;DR: The data suggest that mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth and the exis-tence of both IRS- 1-dependent and IRS-2-independent pathways for signal transduction of insulin and IGFs is suggested.
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Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells
TL;DR: Ppl85 is maximal within seconds after exposure of the cells to insulin and exhibits a dose–response curve similar to that of receptor autophosphorylation, suggesting that this protein represents the endogenous substrate for the insulin receptor kinase.
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The function of GRB2 in linking the insulin receptor to ras signaling pathways
Edward Y. Skolnik,A. Batzer,N. Li,Chi-Hon Lee,E. Lowenstein,Moosa Mohammadi,B. Margolis,Joseph Schlessinger +7 more
TL;DR: Insulin-induced activation of extracellular signal-regulated kinases [ERKs, also known as mitogen-activated protein (MAP) kinases] is mediated by Ras and activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptors to Ras signaling pathways.
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