ACTIVATION OF STRESS-ACTIVATED PROTEIN-KINASE C-JUN N-TERMINAL KINASE, BUT NOT NF-KAPPA-B, BY THE TUMOR-NECROSIS-FACTOR (TNF) RECEPTOR-1 THROUGH A TNF RECEPTOR-ASSOCIATED FACTOR 2-DEPENDENT AND GERMINAL CENTERKINASE RELATED-DEPENDENT PATHWAY

A key step by which tumor necrosis factor (TNF) signals the activation of nuclear factor-kappa B (NF-kappa B) and the stress-activated prote in kinase (SAPK, also called c-Jun N-terminal kinase or JNK) is the re cruitment to the TNF receptor of TNF receptor-associated factor 2 (TRA F2). However, the subsequent steps in TRAF2-induced SAPK and NF-kappa B activation remain unresolved. Here we report the identification of a TNF-responsive serine/threonine protein kinase termed GCK related (GC KR) that likely signals via mitogen-activated protein kinase (MAPK)/ex tracellular signal-regulated kinase (ERK) kinase kinase 1 (MEKK1) to a ctivate the SAPK pathway. TNF, TRAF2, and ultraviolet (UV) light, whic h in part uses the TNF receptor signaling pathway, all increased GCKR activity. A TRAF2 mutant, which inhibits both TRAF2-induced NF-kappa B and SAPK activation, blocked TNF-induced GCKR activation. Finally, in terference with GCKR expression impeded TRAF2- and TNF-induced SAPK ac tivation but not that of NF-kappa B. This suggests a divergence in the TNF signaling pathway that leads to SAPK and NF-kappa B activation, w hich is located downstream of TRAF2 but upstream of GCKR.