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. 2008 Oct;10(10):1199-207.
doi: 10.1038/ncb1780. Epub 2008 Aug 31.

The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner

Alessandro Sorrentino  1 , Noopur Thakur, Susanne Grimsby, Anders Marcusson, Verena von Bulow, Norbert Schuster, Shouting Zhang, Carl-Henrik Heldin, Maréne Landström
Affiliations

The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner

Alessandro Sorrentino et al. Nat Cell Biol. 2008 Oct.

Abstract

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.

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