Chuang L M, Tai T Y, Kahn R C, Wu H P, Lee S C, Lin B J
Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
J Biochem. 1996 Jul;120(1):111-6. doi: 10.1093/oxfordjournals.jbchem.a021371.
IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.
已发现胰岛素受体底物-1（IRS-1）可传递来自胰岛素、胰岛素样生长因子-1、生长激素以及许多细胞因子受体的信号，从而在多种测试细胞类型中产生下游效应。对于白细胞介素4信号传导，大多数研究是在造血细胞和转染了大鼠肝脏IRS-1 cDNA的细胞系上进行的。在肝细胞谱系中，已发现IRS-1在肝癌细胞和再生肝中的肝细胞中表达增加。为了阐明白细胞介素4与胰岛素相比在肝细胞中的可能功能和信号转导途径，我们使用Hep 3B肝癌细胞系作为模型系统。在胰岛素和白细胞介素4刺激后，IRS-1迅速发生酪氨酸磷酸化。白细胞介素4而非胰岛素刺激了JAK1的酪氨酸磷酸化，且对JAK2的刺激程度较小。与其他细胞类型不同，在IL-4和胰岛素刺激Hep3B肝癌细胞后，通过Grb2的SH2结构域证明了IRS-1与Grb2的结合。胰岛素和白细胞介素4均刺激了Erk1激酶的酪氨酸磷酸化和酶活性。我们的结果表明，白细胞介素4和胰岛素可能通过激活JAK激酶的许多不同或共同途径以及使用IRS-1作为对接蛋白来调节肝细胞的生长和分化。IL-4以及胰岛素刺激后IRS-1与Grb2的结合可能导致MAP激酶激活，可能是通过Grb2/sos/p21ras途径。
