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

J Biol Chem. 2002 Nov 22;277(47):44953-61. doi: 10.1074/jbc.M207923200. Epub 2002 Sep 20.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Ectodermal Dysplasia / metabolism
  • Ectodysplasins
  • Edar Receptor
  • Enzyme Activation
  • Genes, Reporter
  • Humans
  • I-kappa B Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Mutation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NF-kappaB-Inducing Kinase
  • Protein Serine-Threonine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptors, Ectodysplasin
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • Xedar Receptor

Substances

  • EDA protein, human
  • EDA2R protein, human
  • EDAR protein, human
  • Ectodysplasins
  • Edar Receptor
  • I-kappa B Proteins
  • Membrane Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proteins
  • Receptors, Ectodysplasin
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • Xedar Receptor
  • NF-KappaB Inhibitor alpha
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases

Associated data

  • GENBANK/AY152724