Human Molecular Genetics Advance Access originally published online on October 26, 2005
Human Molecular Genetics 2005 14(23):3751-3757; doi:10.1093/hmg/ddi405
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TAB2, TRAF6 and TAK1 are involved in NF-
B activation induced by the TNF-receptor, Edar and its adaptator Edaradd
Unité de Recherche sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de sèvres 75015 Paris, France
* To whom correspondence should be addressed at: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries BP10142, 67404 Illkirch Cedex, France. Tel: +33 388653200; Fax: +33 388653201; Email: auroremorlon{at}hotmail.com
Received August 29, 2005; Accepted October 20, 2005
Activation of the NF-
B 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-B transcription factors via an activation of the IB 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 (TGFß-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-B 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-B activation and EDs in human.
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