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.
Sinha
Suwan K
SK
Hamon Center for Therapeutic Oncology Research and Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, USA.
Zachariah
Sunny
S
Quiñones
Herson I
HI
Shindo
Masahisa
M
Chaudhary
Preet M
PM
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004476:Ectodermal Dysplasia / Q000378:metabolism; D053331:Ectodysplasins; D053339:Edar Receptor; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D053340:Xedar Receptor; D000097782:NF-kappaB-Inducing Kinase
D053331:Ectodysplasins; D053339:Edar Receptor; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D053340:Xedar Receptor; D000097782:NF-kappaB-Inducing Kinase; C506018:EDA protein, human; C506011:EDA2R protein, human; C506008:EDAR protein, human; C000606204:NFKBIA protein, human