TAK1 is a ubiquitin-dependent kinase of MKK and IKK

TRAF6 is a signal transducer that activates I kappaB kinase (IKK) and Jun a mino-terminal kinase (JNK) in response to pro-inflammatory mediators such a s interleukin-1 (IL-1) and lipopolysaccharides (LPS)(1-4). IKK activation b y TRAF6 requires two intermediary factors, TRAF6-regulated IKK activator 1 (TRIKA1) and TRIKA2 (ref. 5). TRIKA1 is a dimeric ubiquitin-conjugating enz yme complex composed of Ubc13 and Uev1A (or the functionally equivalent Mms 2). This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism(5). Here we report the purificatio n and identification of TRIKA2, which is composed of TAK1, TAB1 and TAB2, a protein kinase complex previously implicated in IKK activation through an unknown mechanism(6,7). We find that the TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A. Moreo ver, the activity of TAK1 to phosphorylate MKK6, which activates the JNK-p3 8 kinase pathway, is directly regulated by K63-linked polyubiquitination. W e also provide evidence that TRAF6 is conjugated by the K63 polyubiquitin c hains. These results indicate that ubiquitination has an important regulato ry role in stress response pathways, including those of IKK and JNK.