Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line.
We have previously shown that the IL-6R in a growth-responsive B cell line, AF10, induces activation of mitogen-activated protein (MAP) kinase. Here we demonstrate the activation of Raf-1 and MEK-1, which act as a MAP kinase kinase kinase and a MAP kinase kinase, respectively, in the MAP kinase cascade induced by IL-6 in AF10 cells. IL-6 also induced tyrosine phosphorylation of the signaling transducing subunit of the IL-6R in AF10 cells, along with tyrosine phosphorylation of the gp130-associated tyrosine protein kinase JAK1 and the adaptor molecule p52shc. Although induction of tyrosine phosphorylation and activation of MAP kinase by IL-6 in a differentiation-responsive B cell line, SKW 6.4, were below the limits of detection, the phorbol ester PMA did activate Raf-1, MEK-1, and MAP kinase without inducing the phosphorylation of gp130, JAKs, or p52shc. These results suggest that JAK kinase family members associated with the IL-6R may participate in the activation of MAP kinase in AF10 cells by way of an adaptor protein and Ras-dependent kinase cascade.
Department of Medicine, UCLA School of Medicine 90024.
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D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D015153:Blotting, Western; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008934:Mitogens / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D019908:Proto-Oncogene Proteins c-raf; D051575:Proto-Oncogene Proteins c-yes; D019893:Ribosomal Protein S6 Kinases; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000936:Antigen-Antibody Complex; D015850:Interleukin-6; D008934:Mitogens; D011506:Proteins; D011518:Proto-Oncogene Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases