'Make and Brake' in Signaling

摘要

Understanding how cytokines and growth factors trigger intracellular signal transduction is a major challenge in cell biology. Of particular interest is the tumor necrosis factor (TNF)/TNF receptor superfamily, which encompasses more than 20 different ligands and 30 receptors involved in fundamental biological processes including apoptosis, immunity, inflammation, and organogenesis. Ligand binding triggers assembly of multiprotein complexes at the corresponding receptor intracellular domains. The cellular signaling pathways that dictate the biological outcome of ligand binding are thought to be initiated within the receptor-bound complexes and terminated by complex dissociation. A paper by Matsuzawa et al. on page 663 of this issue (1) suggests otherwise. By studying the signaling requirements for CD40, a TNF receptor family member with a prominent role in immune regulation and homeostasis, the authors elegantly demonstrate that activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) cas- cades occurs only upon release of a CD40-teth-ered signaling complex. This two-step mechanism of signal initiation provides new insight into the intricate regulation of receptor-mediated signal transduction.