Role of TRAF3 and -6 in the activation of the NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor.

X-linked ectodermal dysplasia receptor (XEDAR) is a recently isolated member of the tumor necrosis factor receptor family that has been shown to be highly expressed in ectodermal derivatives during embryonic development and binds to ectodysplasin-A2 (EDA-A2). By using a subclone of 293F cells with stable expression of XEDAR, we report ...
that XEDAR activates the NF-kappaB and JNK pathways in an EDA-A2-dependent fashion. Treatment with EDA-A2 leads to the recruitment of TRAF3 and -6 to the aggregated XEDAR complex, suggesting a central role of these adaptors in the proximal aspect of XEDAR signaling. Whereas TRAF3 and -6, IKK1/IKKalpha, IKK2/IKKbeta, and NEMO/IKKgamma are involved in XEDAR-induced NF-kappaB activation, XEDAR-induced JNK activation seems to be mediated via a pathway dependent on TRAF3, TRAF6, and ASK1. Deletion and point mutagenesis studies delineate two distinct regions in the cytoplasmic domain of XEDAR, which are involved in binding to TRAF3 and -6, respectively, and play a major role in the activation of the NF-kappaB and JNK pathways. Taken together, our results establish a major role of TRAF3 and -6 in XEDAR signaling and in the process of ectodermal differentiation.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Line, Ectodermal Dysplasia, Ectodysplasins, Edar Receptor, Enzyme Activation, Genes, Reporter, Humans, I-kappa B Proteins, JNK Mitogen-Activated Protein Kinases, Membrane Proteins, Mitogen-Activated Protein Kinases, Molecular Sequence Data, Mutation, NF-kappa B, Protein-Serine-Threonine Kinases, Proteins, Receptors, Ectodysplasin, Receptors, Tumor Necrosis Factor, Signal Transduction, TNF Receptor-Associated Factor 3, TNF Receptor-Associated Factor 6, Xedar Receptor
J. Biol. Chem.
Date: Nov. 22, 2002
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