IL-6 triggers cell growth via the Ras-dependent mitogen-activated protein kinase cascade.
IL-6 mediates growth of some human multiple myeloma (MM) cells and IL-6-dependent cell lines. Although three IL-6 signaling pathways (STAT1, STAT3, and Ras-dependent MAPK cascade) have been reported, cascades mediating IL-6-triggered growth of MM cells and cell lines are not defined. In this study, we therefore characterized IL-6 signaling cascades in MM cell lines, MM patient cells, and IL-6-dependent B9 cells to determine which pathway mediates IL-6-dependent growth. IL-6 induced phosphorylation of JAK kinases and gp130, regardless of the proliferative response of MM cells to this growth factor. Accordingly, we next examined downstream IL-6 signaling via the STAT3, STAT1, and Ras-dependent mitogen-activated protein kinase (MAPK) cascades. IL-6 triggered phosphorylation of STAT1 and/or STAT3 in MM cells independent of their proliferative response to IL-6. In contrast, IL-6 induced phosphorylation of Shc and its association with Sos1, as well as phosphorylation of MAPK, only in MM cells and B9 cells that proliferated in response to IL-6. Moreover, MAPK antisense, but not sense, oligonucleotide inhibited IL-6-induced proliferation of these cells. These data suggest that STAT1 and/or STAT3 activation may occur independently of the proliferative response to IL-6, and that activation of the MAPK cascade is an important distal pathway for IL-6-mediated growth.
Ogata
A
A
Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Chauhan
D
D
Teoh
G
G
Treon
S P
SP
Urashima
M
M
Schlossman
R L
RL
Anderson
K C
KC
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D005656:Fungal Proteins / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins / Q000378:metabolism; D020837:SOS1 Protein; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C528024:SHC1 protein, human; D020837:SOS1 Protein; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins