Regulation of TGFβ and related signals by precursor processing

•A crystal structure of latent TGFβ explains common regulatory features.•Extracellular storage and maturation of TGFβ and related precursors.•Regulation of precursor processing by substrate-specific inhibitors.•Genetic analysis and live imaging reveal paracrine functions of proprotein convertases.•Protease–substrate interactions are regulated by spatial compartmentalization. Secreted cytokines of the TGFβ family are found in all multicellular organisms and implicated in regulating fundamental cell behaviors such as proliferation, differentiation, migration and survival. Signal transduction involves complexes of specific type I and II receptor kinases that induce the nuclear translocation of Smad transcription factors to regulate target genes. Ligands of the BMP and Nodal subgroups act at a distance to specify distinct cell fates in a concentration-dependent manner. These signaling gradients are shaped by multiple factors, including proteases of the proprotein convertase (PC) family that hydrolyze one or several peptide bonds between an N-terminal prodomain and the C-terminal domain that forms the mature ligand. This review summarizes information on the proteolytic processing of TGFβ and related precursors, and its spatiotemporal regulation by PCs during development and various diseases, including cancer. Available evidence suggests that the unmasking of receptor binding epitopes of TGFβ is only one (and in some cases a non-essential) function of precursor processing. Future studies should consider the impact of proteolytic maturation on protein localization, trafficking and turnover in cells and in the extracellular space.