Interleukin-6 activates phosphoinositol-3' kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways.
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.
Hsu
Jung-Hsin
JH
Department of Medicine, West LA VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90073, USA.
Shi
Yijiang
Y
Frost
Patrick
P
Yan
Huajun
H
Hoang
Bao
B
Sharma
Sanjai
S
Gera
Joseph
J
Lichtenstein
Alan
A
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000201:enzymology*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D015689:Oncogene Protein p21(ras); D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C494086:STAT3 protein, human; C494918:AKT1 protein, human