Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1

  • Argetsinger L
  • Hsu G
  • Myers Jr. M
 et al. 
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The identification of JAK2 as a growth hormone (GH) receptor-associated, GH-activated tyrosine kinase has established tyrosyl phosphorylation as a signaling mechanism for GH. In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts, GH-dependent tyrosyl phosphorylation of IRS-1 was detected by 1 min and at GH concentrations as low as 5 ng/ml (0.23 nM). Tyrosyl phosphorylation of IRS-1 was transient, with maximal stimulation detected at 30 min and diminished signal detected at 60 min. The ability of GH receptor (GHR) to transduce the signal for IRS-1 tyrosyl phosphorylation is mediated by the intracellular region of GHR between amino acids 295 and 380 by a mechanism not involving the two tyrosines in this region. This region of GHR is required for GH-dependent JAK2 association and activation (VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia inhibitory factor. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH, interferon-gamma, and leukemia inhibitory factor and in cells expressing different GHR mutants, provides evidence that IRS-1 may interact with JAK2 or an auxiliary molecule that binds to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well characterized insulin-like metabolic effects of GH observed in a variety of cell types.

Author-supplied keywords

  • *Interleukin-6
  • *Proto-Oncogene Proteins
  • 1-Phosphatidylinositol 3-Kinase
  • Animals
  • CHO Cells
  • Cricetinae
  • Enzyme Activation
  • Growth Hormone/*pharmacology
  • Growth Inhibitors/*pharmacology
  • Humans
  • Insulin Receptor Substrate Proteins
  • Interferon-gamma/*pharmacology
  • Janus Kinase 2
  • Leukemia Inhibitory Factor
  • Lymphokines/*pharmacology
  • Molecular Sequence Data
  • Phosphoproteins/*metabolism
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)/metab
  • Protein-Tyrosine Kinases/metabolism
  • Rats
  • Receptors, Somatotropin/genetics
  • Swine
  • Tyrosine/*metabolism

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  • L S Argetsinger

  • G W Hsu

  • M G Myers Jr.

  • N Billestrup

  • M F White

  • C Carter-Su

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