Interleukin-6 activates phosphoinositol-3' kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways

Oncogene. 2004 Apr 22;23(19):3368-75. doi: 10.1038/sj.onc.1207459.

Abstract

The IL-6-induced activation of the phosphatidylinositol-3' kinase (PI3-K)/AKT cascade in multiple myeloma (MM) cells is critical for tumor cell proliferation and viability. Since the IL-6 receptor does not contain binding sites for the p85 regulatory portion of PI3-K, intermediate molecules must play a role. Coimmunoprecipitation studies in MM cell lines demonstrated the IL-6-induced formation of two independent PI3-K-containing complexes: one containing p21 RAS but not STAT-3 and a second containing STAT-3 but not RAS. Both complexes demonstrated IL-6-induced lipid kinase activity. IL-6 also generated kinase activity in a mutant p110 molecule that could not bind p85. Use of dominant-negative (DN) constructs confirmed the presence of two independent pathways of activation: a DN RAS prevented the IL-6-induced generation of lipid kinase activity in the mutant p110 molecule but had no effect on activity generated in the STAT-3-containing complex. In contrast, a DN p85 prevented the generation of kinase activity in the STAT-3-containing complex but had no effect on activity generated in the p110 molecule. Both DN constructs significantly prevented the IL-6-induced activation of AKT. MM cells expressing activating RAS mutations demonstrated enhanced IL-6-independent growth and constitutive PI3-K activity. These data indicate two potential independent pathways of PI3-K/AKT activation in MM cells: one mediated via signaling through RAS which is independent of p85 and a second mediated via p85 and due to a STAT-3-containing complex.

MeSH terms

  • Cell Line
  • DNA-Binding Proteins / physiology
  • Enzyme Activation
  • Humans
  • Interleukin-6 / pharmacology*
  • Multiple Myeloma / enzymology*
  • Oncogene Protein p21(ras) / physiology*
  • Phosphatidylinositol 3-Kinases / chemistry
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Subunits
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • STAT3 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / physiology

Substances

  • DNA-Binding Proteins
  • Interleukin-6
  • Protein Subunits
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Oncogene Protein p21(ras)