Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 13, Pages 6040-6048Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.13.6040-6048.2004
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Funding
- NCI NIH HHS [T32 CA060395, 5T32CA60395-10] Funding Source: Medline
- NIAID NIH HHS [1 R01 AI057555, R01 AI057555] Funding Source: Medline
- NCHHSTP CDC HHS [U62 PS001145] Funding Source: Medline
- ALLCDC
- NCHHSTP [1U62PS001145-01] Funding Source: Federal RePORTER
- ALLCDC
- NCHHSTP [554634] Funding Source: Federal RePORTER
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IkappaB kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-kappaB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKbeta, but not IKKalpha, is required for Tpl2 activation. Moreover, this novel function of IKKbeta appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-kappaB1/p105. These findings suggest that IKKbeta exerts its immune-regulatory functions by targeting different downstream signaling pathways.
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