西亚试剂：The type I TGF- receptor engages TRAF6 to activate TAK1 in

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

Alessandro Sorrentino^1,3, Noopur Thakur^1,2,3, Susanne Grimsby^1,3, Anders Marcusson^1,2, Verena von Bulow¹, Norbert Schuster¹, Shouting Zhang¹, Carl-Henrik Heldin¹ & Maréne Landström^1,2

Transforming growth factor- (TGF-) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer^{1, 2}. TGF- signals through its Type II and Type I receptors (TRII and TRI) causing phosphorylation of Smad proteins^{3, 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.

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