title: TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.
abstract: Activation of the NF-kappaB pathway by the TNF-receptor Edar (Ectodysplasin receptor) and its downstream adaptator Edaradd (Edar-associated death domain) is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal derivatives. Dysfunction of Edar signalling causes hypohidrotic/anhidrotic ectodermal dysplasia (ED), a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth. The Edar signalling pathway stimulates NF-kappaB transcription factors via an activation of the IkappaB kinase (IKK) complex. To gain further insight into the mechanism of IKK activation by Edar and Edaradd, we performed a yeast two-hybrid screen and isolated TAB2 (TAK1-binding protein 2) as a binding partner of Edaradd. TAB2 is an adaptator protein that brigdes TRAF6 (TNF-receptor-associated factor 6) to TAK1 (TGFbeta-activated kinase 1), allowing TAK1 activation and subsequent IKK activation. Here, we show that endogenous and overexpressed TAB2, TRAF6 and TAK1 co-immunoprecipitated with Edaradd in 293 cells. Moreover, we show that dominant negative forms of TAB2, TRAF6 and TAK1 blocked the NF-kappaB activation induced by Edaradd. These results support the involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway and have important implications for our understanding of NF-kappaB activation and EDs in human.
authors.affiliation: Unité de Recherche sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de sèvres 75015 Paris, France. auroremorlon@hotmail.com
authors.forename: Aurore
authors.initials: A
authors.lastname: Morlon
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Asma
authors.initials: A
authors.lastname: Smahi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004476:Ectodermal Dysplasia / Q000378:metabolism*; D053339:Edar Receptor; D053362:Edar-Associated Death Domain Protein; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053339:Edar Receptor; D053362:Edar-Associated Death Domain Protein; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D048029:TNF Receptor-Associated Factor 6; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000099151:MAP Kinase Kinase Kinase 7; C506008:EDAR protein, human; C506125:EDARADD protein, human; C410585:TAB2 protein, human