Journal Article

TAB2, TRAF6 and TAK1 are involved in NF-<i>κ</i>B activation induced by the TNF-receptor, Edar and its adaptator Edaradd

Aurore Morlon, Arnold Munnich and Asma Smahi

in Human Molecular Genetics

Volume 14, issue 23, pages 3751-3757
Published in print December 2005 | ISSN: 0964-6906
Published online October 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi405
TAB2, TRAF6 and TAK1 are involved in NF-κB activation induced by the TNF-receptor, Edar and its adaptator Edaradd

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Activation of the NF-κB 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-κB transcription factors via an activation of the IκB 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 (TGFβ-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-κB 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-κB activation and EDs in human.

Journal Article.  3735 words.  Illustrated.

Subjects: Genetics and Genomics

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