Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain
Year: 1999
Type: preprint
Abstract: Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappaB through activation of the MAP kinases JNK and p38 and the IkappaB kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.
Source: Genes & Development
Authors: V. Baud, Z.-G. Liu, B. Bennett, N. Suzuki, Y. Xia, M. Karin
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
Awards: G5738367093, INTERACTIONS OF HEAVY METAL IONS WITH THE HUMAN GENOME , G6471017998, Regulation of NF-kappaB and IKK by proinflammatory stimuli, G6964015019, TISSUE SPECIFIC EXPRESSION OF GROWTH HORMONE GENE, G9000101246, G9000141551, NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation
OpenAlex ID: W2116063836