title: The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden, Dag Hammarskjöldsv. 20, SE-75185 Uppsala, Sweden.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sorrentino
authors.forename: Noopur
authors.initials: N
authors.lastname: Thakur
authors.forename: Susanne
authors.initials: S
authors.lastname: Grimsby
authors.forename: Anders
authors.initials: A
authors.lastname: Marcusson
authors.forename: Verena
authors.initials: V
authors.lastname: von Bulow
authors.forename: Norbert
authors.initials: N
authors.lastname: Schuster
authors.forename: Shouting
authors.initials: S
authors.lastname: Zhang
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Maréne
authors.initials: M
authors.lastname: Landström