Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor alpha [corrected].
Interleukin-6 (IL-6) is a growth and antiapoptotic factor for human myeloma cells. The autocrine loop and increased expression of the growth factor receptors have been postulated as the mechanisms of tumorigenesis. Here we show that IL-6 stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2, highly expressing IL-6 receptor alpha (IL-6R alpha) and in the IL-6R alpha-transfected U266 cell line. IL-6-dependent complex formation of IL-6R alpha with IGF-I receptor beta was found in NOP2 where IL-6R alpha colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6-induced phosphorylation of IGF-I receptor beta was not blocked by a Janus kinase 2 (Jak2) inhibitor. In addition to the activation of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, IL-6 stimulation led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6R alpha and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6. The synergistic effects of highly expressed IL-6R alpha on IGF-I receptor-mediated signals provide a novel insight into the Jak-independent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells.
Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan.
Saeid
S
Abroun
Hideaki
H
Ishikawa
Naohiro
N
Tsuyama
Shangqin
S
Liu
Fu-Jun
FJ
Li
Ken-ichiro
K
Otsuyama
Xu
X
Zheng
Masanori
M
Obata
Michio M
MM
Kawano
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D053222:Fas Ligand Protein; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D053222:Fas Ligand Protein; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D017526:Receptor, IGF Type 1; D019947:Receptors, Interleukin-6; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C493956:CDKN1A protein, human; C505661:FASLG protein, human; C494918:AKT1 protein, human