Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1

• Published in: Nature (London) 1994-11, Vol.372 (6502), p.182-186
• Main Authors: Tamemoto, H, Kadowaki, T, Tobe, K, Yagi, T, Sakura, H, Hayakawa, T, Kaburagi, Y, Terauchi, Y, Ueki, K, Satoh, S
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; binding proteins; Biological and medical sciences; Blood Glucose - metabolism; Cell physiology; Female; Fetal Growth Retardation - physiopathology; Fundamental and applied biological sciences. Psychology; Genes; Growth - physiology; Growth Disorders - physiopathology; Growth factors; Heterozygote; Homozygote; Hormonal regulation; hormone receptors; Humanities and Social Sciences; Insulin; Insulin - physiology; Insulin Receptor Substrate Proteins; Insulin Resistance - physiology; Insulin-Like Growth Factor I - physiology; Insulin-Like Growth Factor II - physiology; irs-1 gene; kinases; letter; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Molecular and cellular biology; Molecular Sequence Data; multidisciplinary; mutagenesis; Mutation; Phosphoproteins - deficiency; Phosphoproteins - physiology; phsophatidylinositol-3-oh kinase; Physical growth; Physiology; Receptor, Insulin - physiology; resistance; Rodents; Science; Science (multidisciplinary); Signal Transduction - physiology; structural genes; Substrates; Translocation; tyrosine kinase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/372182a0

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 (Mr, 160-190K) on SDS polyacrylamide gel. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phsophatidylinositol 3-kinase which may be involved in the translocation of glucose transporters and the abundant src homology protein (ASH)/Grb2 which may be involved in activation of p21ras anad MAP kinase cascde. IRS-1 also has binding sites for Syp and Nck and other src homology 2 (SH2) signalling molecules. To clarify the physiological roles 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 existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.