Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Nature. 1994 Nov 10;372(6502):182-6. 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 (M(r), 160-190K) on SDS polyacrylamide gel. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 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 and MAP kinase cascade. IRS-1 also has binding sites for Syp and Nck and other src homology 2 (SH2) signalling molecules. 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 existence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.
胰岛素受体底物-1（IRS-1）是胰岛素受体和胰岛素样生长因子-1（IGF-1）受体酪氨酸激酶的主要底物；在十二烷基硫酸钠-聚丙烯酰胺凝胶上，其表观相对分子质量为160000 - 190000（M(r)，160K - 190K）。酪氨酸磷酸化的IRS-1可结合磷脂酰肌醇3激酶的85K亚基，这可能参与葡萄糖转运体的转位；还可结合富含src同源结构域的蛋白（ASH）/Grb2，这可能参与p21ras和丝裂原活化蛋白激酶（MAP）级联反应的激活。IRS-1也有与Syp和Nck以及其他src同源结构域2（SH2）信号分子的结合位点。为阐明IRS-1在体内的生理作用，我们构建了IRS-1基因位点靶向敲除的小鼠。IRS-1基因靶向敲除的纯合子小鼠存活出生，但胚胎期和出生后的生长发育迟缓。它们对胰岛素、IGF-1和IGF-2的降糖作用也有抵抗。这些数据提示胰岛素和IGF信号转导存在依赖IRS-1和不依赖IRS-1的途径。
