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Human Molecular Genetics Advance Access published online on October 26, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi405
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 29, 2005
Revised October 19, 2005
Accepted October 20, 2005

Article

TAB2, TRAF6 and TAK1 are involved in NF-{kappa}B activation induced by the TNF-receptor, Edar, and its adaptator Edaradd

Aurore Morlon 1*, Arnold Munnich 2, and Asma Smahi 2

1 Unité de Recherche sur les Handicaps Génétiques de l'Enfant INSERM U-393, Hôpital Necker-Enfants Malades, 149 rue de sèvres 75015 Paris, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries BP10142, 67404 Illkirch Cedex, France
2 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.
Aurore Morlon, E-mail: auroremorlon{at}hotmail.com


  Abstract

Activation of the NF-{kappa}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, a disorder characterized by sparse hair, lack of sweat glands and malformation of teeth. The Edar signalling pathway stimulates NF-{kappa}B transcription factors via an activation of the I{kappa}B kinase complex (IKK). 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 (TGF{beta}-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-{kappa}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-{kappa}B activation and Ectodermal Dysplasias in human.


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