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The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
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2008 (English)In: Nature Cell Biology, ISSN 1465-7392, Vol. 10, no 10, 1199-1207 p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-beta signals through its Type II and Type I receptors (TbetaRII and TbetaRI) causing phosphorylation of Smad proteins. TGF-beta-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-beta-induced p38 activation. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TbetaRI. The TbetaRI-TRAF6 interaction is required for TGF-beta-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1-p38/JNK pathway, which leads to apoptosis. TbetaRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

Place, publisher, year, edition, pages
2008. Vol. 10, no 10, 1199-1207 p.
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URN: urn:nbn:se:umu:diva-36644DOI: 10.1038/ncb1780PubMedID: 18758450OAI: oai:DiVA.org:umu-36644DiVA: diva2:355457
Available from: 2010-10-06 Created: 2010-10-06 Last updated: 2011-09-02Bibliographically approved

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Landström, Maréne

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