Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1 (original) (raw)

• Letter
• Published: 10 November 1994
• Takashi Kadowaki1,
• Kazuyuki Tobe1,
• Takeshi Yagi2 nAff6,
• Hiroshi Sakura1,
• Takaki Hayakawa1 nAff8,
• Yasuo Terauchi1,
• Kohjiro Ueki1,
• Yasushi Kaburagi1,
• Shinobu Satoh4,
• Hisahiko Sekihara4,
• Shinji Yoshioka3,
• Hiroyoshi Horikoshi3,
• Yasuhide Furuta2 nAff7,
• Yoji Ikawa2,
• Masato Kasuga5,
• Yoshio Yazaki1 &
• …
• Shinichi Aizawa2 nAff7

Nature volume 372, pages 182–186 (1994) Cite this article

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Abstract

INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent relative molecular mass of 160–190,000 (M_r, 160–190K) on SDS polyacrylamide gel1–3. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase4,5 which may be involved in the translocation of glucose transporters6,7 and the abundant src homology protein (ASH)/Grb28,9 which may be involved in activation of p2l_ras and MAP kinase cascade10. IRS-1 also has binding sites for Syp11 and Nck12 and other src homology 2 (SH2) signalling molecules10. To clarify the physiological roles of IRS-1 in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the exis-tence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.

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Author information

Author notes

1. Takeshi Yagi
   Present address: Department of Neurobiology and Behavioral Genetics, National Institute for Physiological Science, Myodaiji, Okazaki, 444, Japan
2. Yasuhide Furuta & Shinichi Aizawa
   Present address: Laboratory of Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University School of Medicine, Kumamoto, 860, Japan
3. Takaki Hayakawa
   Present address: Pharmaceutical Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka, 532, Japan

Authors and Affiliations

1. The Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo, Tokyo, 113, Japan
   Hiroyuki Tamemoto, Takashi Kadowaki, Kazuyuki Tobe, Hiroshi Sakura, Takaki Hayakawa, Yasuo Terauchi, Kohjiro Ueki, Yasushi Kaburagi & Yoshio Yazaki
2. Laboratory of Molecular Oncology, Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), Tsukuba, Ibaraki, 305, Japan
   Hiroyuki Tamemoto, Takeshi Yagi, Yasuhide Furuta, Yoji Ikawa & Shinichi Aizawa
3. Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd, Shinagawa, Tokyo, 140, Japan
   Shinji Yoshioka & Hiroyoshi Horikoshi
4. The Third Department of Internal Medicine, Faculty of Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa, 236, Japan
   Shinobu Satoh & Hisahiko Sekihara
5. The Second Department of Internal Medicine, Faculty of Medicine, University of Kobe, Kobe, Hyogo, 650, Japan
   Masato Kasuga

Authors

1. Hiroyuki Tamemoto
2. Takashi Kadowaki
3. Kazuyuki Tobe
4. Takeshi Yagi
5. Hiroshi Sakura
6. Takaki Hayakawa
7. Yasuo Terauchi
8. Kohjiro Ueki
9. Yasushi Kaburagi
10. Shinobu Satoh
11. Hisahiko Sekihara
12. Shinji Yoshioka
13. Hiroyoshi Horikoshi
14. Yasuhide Furuta
15. Yoji Ikawa
16. Masato Kasuga
17. Yoshio Yazaki
18. Shinichi Aizawa

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Tamemoto, H., Kadowaki, T., Tobe, K. et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1.Nature 372, 182–186 (1994). https://doi.org/10.1038/372182a0

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• Received: 13 June 1994
• Accepted: 08 September 1994
• Issue date: 10 November 1994
• DOI: https://doi.org/10.1038/372182a0