Tumor necrosis factor-alpha activation of nuclear transcription factor-kappaB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of Ikappa Balpha.
Tumor necrosis factor-alpha (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-kappa B (NF-kappaB). NF-kappaB is sequestered in the cytosol by Ikappa Balpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation. In contrast, we find TNF induction of NF-kappaB in murine bone marrow macrophages (BMMs), is mediated, by c-Src, in a cell, and cytokine specific manner. The non-receptor tyrosine kinase is rapidly mobilized and activated upon TNF exposure. Within the same time frame, TNF induced c-Src associates with Ikappa Balpha in a long lived complex. The proto-oncogene, when associated with Ikappa Balpha phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced Ikappa Balpha tyrosine phosphorylation, NF-kappaB activation, by the cytokine, is markedly delayed and reduced in c-src-/- BMMs. Underscoring the physiological significance of c-Src activation of NF-kappaB, TNF induction of IL-6, which is an NF-kappaB mediated event, is substantially diminished in c-src-/- BMMs.
Abu-Amer
Y
Y
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. abuamery@medicine.wustl.edu
Ross
F P
FP
McHugh
K P
KP
Livolsi
A
A
Peyron
J F
JF
Teitelbaum
S L
SL
D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)