Signal Transduction Pathways for Interleukin 4 and Insulin in Human Hepatoma Cells

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    • CHUANG Lee-Ming
    • Department of Internal Medicine, College of Medicine, National Taiwan University
    • TAI Tong-Yuan
    • Department of Internal Medicine, College of Medicine, National Taiwan University
    • KAHN Ronald C.
    • Research Division, Joslin Diabetes Center, Department of Medicine and Department of Molecular and Cellular Physiology, Harvard Medical School
    • WU Huey-Peir
    • Department of Internal Medicine, College of Medicine, National Taiwan University
    • LEE Sheng-Chung
    • Graduate Institute of Molecular Medicine, College of Medicine, National Taiwan University
    • LIN Boniface J.
    • Graduate Institute Clinical Meidicine, College of Medicine, National Taiwan University


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/p21<sup>ras</sup> pathway.


  • The Journal of Biochemistry

    The Journal of Biochemistry 120(1), 111-116, 1996-07-01

    The Japanese Biochemical Society

References:  41


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