Joan Massagué - TGF-β Signaling in Development, Immunity and Cancer

Few cell signals match the impact of the TGF-β _ENREF_1 family in metazoan biology. TGF-β cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions, and various congenital diseases. The effects of the TGF-β _ENREF_1 family are mediated by a combinatorial set of ligands and receptors, and a common set of receptor-activated SMAD transcription factors. Yet, the effects can dramatically differ depending on the cell type and the conditions. Recent progress has illuminated a model of TGF-β action in which SMADs bind genome-wide in partnership with lineage-determining transcription factors and additionally integrate inputs from other pathways and the chromatin to trigger specific cellular responses. We will review recent progress in understanding the context-dependent interpretation of TGF-β signals in embryonic stem cells, immune regulation, tumor suppression, and metastasis. The new insights clarify the operating logic of the TGF-β system in physiology and disease.