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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2291-2298.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-07-2187.
Submitted July 1, 2003
Accepted October 28, 2003
Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in the IL-6 receptor  highly expressing myeloma cells
Saeid Abroun, Hideaki Ishikawa*, Naohiro Tsuyama, Shangqin Liu, Fu-Jun Li, Ken-ichiro Otsuyama, Xu Zheng, Masanori Obata, and Michio M Kawano
Department of Bio-Signal Analysis (Immunohematology), Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, Ube, Japan
* Corresponding author; email: hishika{at}yamaguchi-u.ac.jp.
Interleukin-6 (IL-6) is a growth and anti-apoptotic 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  (IL-6R) and in the IL-6R-transfected U266 cell line. IL-6-dependent complex formation of IL-6R with IGF-I receptor  was found in NOP2 where IL-6R colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6-induced phosphorylation of IGF-I receptor 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 led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6R and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of two receptors in response to IL-6. The synergistic effects of highly expressed IL-6R 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.
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