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
Open Access
- 15 May 1999
- journal article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 13 (10), 1297-1308
- https://doi.org/10.1101/gad.13.10.1297
Abstract
Interleukin-1 (IL-1) and tumor necrosis factor (TNF-α) stimulate transcription factors AP-1 and NF-κB through activation of the MAP kinases JNK and p38 and the IκB kinase (IKK), respectively. The TNF-α 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-α and IL-1 responsive genes. TNF-α also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-α and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.Keywords
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