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

H Tamemoto, T Kadowaki, K Tobe, T Yagi, H Sakura… - Nature, 1994 - nature.com
H Tamemoto, T Kadowaki, K Tobe, T Yagi, H Sakura, T Hayakawa, Y Terauchi, K Ueki…
Nature, 1994nature.com
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 …
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 (Mr, 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 p2lras 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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