Kinase-Independent Signaling from TGF-β Receptors to TAK1

Science Signaling  07 Oct 2008:
Vol. 1, Issue 40, pp. ec348
DOI: 10.1126/scisignal.140ec348

Transforming growth factor-β (TGF-β) signals through its receptor, composed of the type I and type II subunits (TβRI and TβRII), to stimulate a pathway involving Smads, as well as Smad-independent signaling. Sorrentino et al. found that in cells transfected with TAK1 [TGF-β-associated kinase 1, a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family that is upstream of p38 and ubiquitin], TGF-β1 stimulated the ubiquitylation of TAK1, as well as the phosphorylation of TAK1, which is an indication of activation. When a mutant form of ubiquitin that could not form Lys63-linked chains was transfected into the cells, TAK1 ubiquitylation and phosphorylation, recruitment of TAB2 (TAK-associated binding protein 2), and activation of p38 was diminished. Pharmacological inhibition of TβRI kinase activity failed to block TGF-β-stimulated TAK1 and p38 activation but did block Smad activation, suggesting that activation of the p38 MAPK pathway was independent of the kinase activity of the receptor. The E3 ubiquitin ligase TRAF6 interacted with TβRI even in the absence of ligand. A consensus TRAF6 binding motif in TβRI was identified and mutations in this motif blocked the interaction between TRAF6 and TβRI; cells expressing this form of TβRI failed to promote p38 or TAK1 phosphorylation in response to TGF-β. Overexpression of a dominant-negative TRAF6 also blocked TGF-β-mediated activation of p38 and TAK1. Confirmation of the importance of TRAF6 was also obtained by experiments with TRAF6-deficient mouse embryo fibroblasts or by knocking down TRAF6 with short interfering RNAs. In both cases, activation of TAK1 and p38 and the subsequent apoptotic response to TGF-β were diminished. Thus, TGF-β appears to trigger activation of a MAPK pathway through a process involving the activation of the TRAF6 E3 ubiquitin ligase associated with TβRI and promotion of Lys63-linked polyubiquitylation of TAK1.

A. Sorrentino, N. Thakur, S. Grimsby, A. Marcusson, V. von Bulow, N. Schuster, S. Zhang, C.-H. Heldin, M. Landström, The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199-1207 (2008). [PubMed]