Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line
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Ectodermal Dysplasia / metabolism
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Ectodysplasins
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Edar Receptor
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Enzyme Activation
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Genes, Reporter
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Humans
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I-kappa B Proteins / metabolism
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JNK Mitogen-Activated Protein Kinases
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Membrane Proteins / pharmacology
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Mitogen-Activated Protein Kinases / metabolism*
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Molecular Sequence Data
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Mutation
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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NF-kappaB-Inducing Kinase
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism*
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Receptors, Ectodysplasin
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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Xedar Receptor
Substances
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EDA protein, human
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EDA2R protein, human
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EDAR protein, human
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Ectodysplasins
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Edar Receptor
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I-kappa B Proteins
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Membrane Proteins
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NF-kappa B
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NFKBIA protein, human
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Proteins
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Receptors, Ectodysplasin
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 3
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TNF Receptor-Associated Factor 6
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Xedar Receptor
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NF-KappaB Inhibitor alpha
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Protein Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases