TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-β

In many physiological and disease processes, TGF-beta usurps branches of MAP kinase pathways in conjunction with Smads to induce apoptosis and epithelial-to-mesenchymal transition, but the detailed mechanism of how a MAP kinase cascade is activated by TGF-beta receptors is not clear. We report here that TRAFIS is specifically required for the Smad-independent activation of JNK and p38, and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors. TGF-beta induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAKII. Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1 beta/Tolllike receptor pathway.