Cover: Scheme for cytokine-driven MAPK-dependent pathways that regulate cellular apoptosis (red) and survival (blue). Each of the three MAPK signaling cascades (labeled 1-3) are organized into three-tiered modules that begin with receptor-linked MAPKKK activation followed by MAPKK activation and then MAPK activation. TGF-ß binding to its receptor leads to activation of each of the three MAPK cascades with predominant activation of p38-MAPK (labeled 2) and lesser activation of SAPK/JNK and ERK (labeled 1 and 3). This set of signals causes a pattern of transcription factor (TF) activation (labeled A, B, and C) and consequent gene expression of factors that act on downstream mitochondrial and caspase targets to cause apoptosis. MAPK pathways may also act at a post-translational level (e.g., SAPK/JNK action on BCL-2) to influence apoptosis. Because inhibitors of each MAPK pathway can block TGF-ß–induced apoptosis, each of these pathways appears necessary but not sufficient for causing apoptosis. Other types of cytokines (and TGF-ß itself in other systems) can activate other receptor/adaptor systems linked to MAPK signals that are anti-apoptotic and promote cell survival. This link in the ERK pathway (labeled with ?) and the site of glucocorticoid (GC) action to block MAPK-dependent apoptosis still need to be determined. For more information see Perspective by O'Sullivan and coworkers beginning on page 3.