TGF-β signaling: A new route to p38 and JNK
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TGF-β activates p38/JNK through TRAF6-mediated polyubiquitylation of TAK1.
Transforming growth factor-β (TGF-β) is a dimeric cytokine that induces the dimerization and cross-phosphorylation of its cellular receptors, TGF-β receptor Type I and II (TβRI and TβRII). Activated TβRI/TβRII then phosphorylates receptor-associated (R)-Smad proteins, promoting their nuclear translocation and gene regulation. TGF-β associated kinase (TAK1) activates p38 and c-Jun N-terminal protein kinase (JNK) in response to TGF-β, leading to apoptosis. The ubiquitin ligase TRAF6 (tumor necrosis factor (TNF) receptor-associated factor-6) has been implicated in the activation of TAK1 by interleukin-1, but the mechanism of TAK1 activation by TGF-β has remained elusive. Reporting in Nature Cell Biology, Sorrentino et al. now identify a kinase-independent pathway of TGF-β receptor signaling that connects auto-ubiquitylation of TRAF6 with the polyubiquitylation of TAK1 and the activation of p38.
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The authors observed that TAK1 underwent lysine 63-linked polyubiquitylation in response to TGF-β, which correlated with the phosphorylation and activation of both TAK1 and p38. Chemical inhibitors of TβRI kinase activity and kinase-deficient TβRI mutants inhibited the activation of Smad proteins — but not of TAK1 or p38 — suggesting that the pathway does not require TβRI kinase activity. Consistent with previous studies, TGF-β induced TRAF6 auto-ubiquitylation and activation. Point mutations in the TRAF6 binding motif of TβRI abrogated TAK1 and p38 activation, suggesting that the association between TRAF6 and TβRI is necessary for TAK1 activation. TRAF6-deficient cells demonstrated defects in TAK1 and p38 activation, as well as in TGF-β-induced apoptosis. The authors found that TAK1 was directly ubiquitylated by TRAF6 in vitro, and that TAK1 activation required both TRAF6 E3-ligase activity and the presence of the TAK1 ubiquitin acceptor site.
The authors propose that TGF-β binding to TβRI induces the auto-ubiquitylation of TRAF6 and subsequent TRAF6-mediated polyubiquitylation of TAK1. Phosphorylation of TAK1 completes TAK1 activation and leads to p38 activation and apoptosis. Thus, TβRI has a dual role: its kinase activity is required for signaling and gene transcription via the Smad proteins, but is not required for TRAF6-mediated activation of TAK1 and apoptosis. Further dissection of the TGF-β pathway is necessary to identify the mechanism of TAK1 phosphorylation following ubiquitylation by TRAF6.
Anna S. Kushnir
Nature Publishing Group
Reference
- Sorrentino, A. et al. The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nature Cell Biology 10, 1199-1207 (2008) | Article | PubMed |
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