PROTEIN-KINASE CASCADES ACTIVATED BY STRESS AND INFLAMMATORY CYTOKINES

Signal transduction pathways constructed around a core module of three consecutive protein kinases, the most distal being a member of the ex tracellular signal-regulated kinase (ERK) family, are ubiquitous among eukaryotes. Recent work has defined two cascades activated preferenti ally by the inflammatory cytokines TNF-alpha and IL-1-beta, as well as by a wide variety of cellular stresses such as UV and ionizing radiat ion, hyperosmolarity, heat stress, oxidative stress, etc, One pathway converges on the ERK subfamily known as the 'stress activated' protein kinases (SAPKs, also termed Jun N-terminal kinases, JNKs), whereas th e second pathway recruits the p38 kinases, Upstream inputs are diverse , and include small GTPases (primarily Rac and Cdc42; secondarily Ras) acting through mammalian homologs of the yeast Ste20 kinase, other ki nase subfamilies (e.g. GC kinase) and ceramide, a putative second mess enger for certain TNF-alpha actions. These two cascades signal cell cy cle delay, cellular repair or apoptosis in most cells, as well as acti vation of immune and reticuloendothelial cells.