Sounding the Alarm: Protein Kinase Cascades Activated by Stress and Inflammation

Abstract

Eukaryotic cells respond to extracellular stimuli by recruiting signal transduction pathways, many of which employ protein Ser/Thr kinases of the ERK(1) family. The ubiquity of ERKs and their upstream activators, the MEKs, in signal transduction was first appreciated from studies of yeast (1, 2). Although a 54-kDa rat liver c-Jun kinase (SAPK-p54 alpha 1) with properties similar to the Ras-regulated MAPKs had been characterized (3-5), the physiologic roles and regulation of this and related mammalian enzymes have emerged only recently. Molecular cloning of the SAPKs and p38s, together with the paradigms derived from the ''classical'' MAPKs and work in lower eukaryotes has enabled rapid elucidation of the regulation and cellular functions of these newer mammalian ERK pathways. Although architecturally homologous to the Ras/MAPK pathway, the SAPK and p38 pathways are not activated primarily by mitogens but by cellular stresses and inflammatory cytokines, which stimuli result in growth arrest, apoptosis, or activation of immune and reticuloendothelial cells.