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

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antigens, CD / physiology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Carcinoma, Hepatocellular / metabolism
  • Enzyme Activation / drug effects
  • GRB2 Adaptor Protein
  • Humans
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Interleukin-4 / pharmacology*
  • Janus Kinase 1
  • Janus Kinase 2
  • Liver / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Myelin Basic Protein / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins*
  • Receptors, Interleukin / physiology
  • Receptors, Interleukin-4
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • src Homology Domains


  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Myelin Basic Protein
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Interleukin
  • Receptors, Interleukin-4
  • Interleukin-4
  • Tyrosine
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • JAK2 protein, human
  • Jak1 protein, rat
  • Jak2 protein, rat
  • Janus Kinase 1
  • Janus Kinase 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases