Tumor necrosis factor-α activation of nuclear transcription factor-κB in marrow macrophages is mediated by c-Src tyrosine phosphorylation of IκBα

Yousef Abu-Amer, F. Patrick Rossl, Kevin P. McHugh, Antonia Livolsi, Jean Francois Peyron, Steven L. Teitelbaum

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Tumor necrosis factor-α (TNF) exerts its transcriptional effects via activation of nuclear transcription factor-κ B (NF-κB). NF-κB is sequestered in the cytosol by IκBα 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- κB 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 IκBα in a long lived complex. The proto-oncogene, when associated with IκBα phosphorylates the inhibitory protein on tyrosine 42. Consistent with the pivotal role played by c-Src in TNF-induced IκBα tyrosine phosphorylation, NF-κB activation, by the cytokine, is markedly delayed and reduced in c-src-/BMMs. Underscoring the physiological significance of c-Src activation of NF-κB, TNF induction of IL-6, which is an NF-κB mediated event, is substantially diminished in c- src-/- BMMs.

Original languageEnglish
Pages (from-to)29417-29423
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number45
DOIs
StatePublished - Nov 6 1998

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