Letter abstract
Nature Cell Biology 10, 1199 - 1207 (2008)
Published online: 31 August 2008 | doi:10.1038/ncb1780
The type I TGF-
receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
Alessandro Sorrentino1,3, Noopur Thakur1,2,3, Susanne Grimsby1,3, Anders Marcusson1,2, Verena von Bulow1, Norbert Schuster1, Shouting Zhang1, Carl-Henrik Heldin1 & Maréne Landström1,2
Transforming growth factor-
(TGF-) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer1, 2. TGF- signals through its Type II and Type I receptors (TRII and TRI) causing phosphorylation of Smad proteins3, 4. TGF--associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF--induced p38 activation5. 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 TRI. The TRI–TRAF6 interaction is required for TGF--induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis. TRI 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--induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF- specifically activates TAK1 through interaction of TRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.
- Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden, Dag Hammarskjöldsv. 20, SE-751 85 Uppsala, Sweden.
- Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden, Dag Hammarskjöldsv. 20, SE-751 85 Uppsala, Sweden.
- These authors contributed equally to this work.
Correspondence to: Maréne Landström1,2 e-mail: Marene.Landstrom@genpat.uu.se
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