Authors:
Alessandro Sorrentino, Noopur Thakur, Susanne Grimsby, Anders Marcusson, Verena von Bulow, Norbert Schuster, Shouting Zhang, Carl-Henrik Heldin, & Maréne Landström
Summary:
Transforming growth factor-b (TGF-b) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-b signals through its Type II and Type I receptors (T RII and T RI) causing phosphorylation of Smad proteins. TGF-b-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-b-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 T RI. The T RI–TRAF6 interaction is required for TGF-b-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis. T RI 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-b-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-b specifically activates TAK1 through interaction of T RI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.
Source:
Nature Cell Biology; 10, 1199 – 1207 (08/31/08)