ASK1 IS ESSENTIAL FOR JNK SAPK ACTIVATION BY TRAF2/

Tumor necrosis factor (TNF)-induced activation of the c-jun N-terminal kinase (JNK, also known as SAPK; stress-activated protein kinase) req uires TNF receptor-associated factor 2 (TRAF2). The apoptosis signal-r egulating kinase 1 (ASK1) is activated by TNF and stimulates JNK activ ation. Here we show that ASK1 interacts with members of the TRAF famil y and is activated by TRAF2, TRAF5, and TRAF6 overexpression. A trunca ted derivative of TRAF2, which inhibits JNK activation by TNF, blocks TNF-induced ASK1 activation. A catalytically inactive mutant of ASK1 i s a dominant-negative inhibitor of TNF- and TRAF2-induced JNK activati on. In untransfected mammalian cells, ASK1 rapidly associates with TRA F2 in a TNF-dependent manner. Thus, ASK1 is a mediator of TRAF2-induce d JNK activation.