ArticleProceedings of the National Academy of Sciences of the United States of America2000
Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 177 citations in OpenAlex.
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- Possible Role of Raf-1 Kinase in the Development of Cerebral Vasospasm and Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats.Molecular neurobiology · 2015Article
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Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NF-kappaB is regulated by inhibitor proteins (IkappaBs), which retain NF-kappaB in the cytoplasm. Signal-induced phosphorylation by the IkappaB-kinase complex containing the IkappaB-kinases 1 and 2 (IKK-1/2 or IKK-alpha/beta) and subsequent degradation of the IkappaB proteins are prerequisites for NF-kappaB activation. Many signals induce NF-kappaB, one of them being oncogenic Raf kinase. We investigated whether NF-kappaB induction is critical for Raf-mediated transformation. Here, we demonstrate that inhibition of NF-kappaB interferes with transformation by the Raf-oncogene, and we characterized the mechanism of NF-kappaB induction by activated Raf kinase and the tumor promoter phorbol 12-myristate 13-acetate (PMA). NF-kappaB activation by PMA and Raf critically depends on the IkappaB-kinase complex, most notably on IKK-2. A major signaling pathway induced by Raf is the mitogenic cytoplasmic kinase cascade. However, different inhibitors of this cascade do not affect PMA- and Raf-mediated NF-kappaB activation. Raf does not phosphorylate the IkappaB-kinase proteins directly. Raf rather synergizes with another membrane shuttle kinase MEKK1, and Raf-mediated activation of NF-kappaB is blocked by a dominant negative form of MEKK1. These results suggest that Raf induction of NF-kappaB is relayed by MEKK1, but not by the classical mitogenic cytoplasmic kinase cascade.
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