Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation.
Multiple myeloma (MM) is a proliferative disorder of monoclonal plasma cells which accumulate in human bone marrow, and myeloma cells proliferate in response to a cytokine, interleukin-6 (IL-6). We recently found that MPC-1- CD49e- immature myeloma cells expressing CD45 form a proliferating population in MM. IL-6 activates at least two intracellular pathways including signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase 1/2 (ERK1/2) following the activation of Janus kinases (JAKs) via its receptor complexes composed of the IL-6 receptor alpha chain and gp130. Although the roles of CD45 have been extensively studied for antigen receptors in B and T cells, its physiological consequences in other hematopoietic cells remain largely unknown. Myeloma cells expressing CD45 antigens which contain the activation of src family protein-tyrosine kinases (PTKs) independent of IL-6 stimulation proliferate in response to IL-6, whereas the proliferation of CD45- cells which lack a considerable activity of the src family PTKs is not promoted by IL-6. The STAT3 and ERK1/2 pathways are similarly activated by IL-6 in both cells either expressing or not expressing CD45. In this review, we argue a novel mechanism of proliferation of myeloma cells, in that the activation of both STAT3 and ERK1/2 is not sufficient for IL-6-induced proliferation which further requires IL-6-independent activation of the src family kinases associated with CD45 phosphatase. We propose that the cellular context, such as CD45 expression and src family kinase activation, is crucial for myeloma cells to proliferate in response to IL-6.
Ishikawa
Hideaki
H
Department of Bio-Signal Analysis, Applied Medical Engineering Science, Graduate School of Medicine, Yamaguchi University, 1-1-1 Minami-kogushi, Ube, Yamaguchi 755-8505, Japan. hishika@yamaguchi-u.ac.jp
Tsuyama
Naohiro
N
Abroun
Saeid
S
Liu
Shangqin
S
Li
Fu-Jun
FJ
Otsuyama
Ken-Ichiro
K
Zheng
Xu
X
Kawano
Michio M
MM
D015703:Antigens, CD / Q000502:physiology; D002455:Cell Division; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens