title: Regulation of TGFβ and related signals by precursor processing.
abstract: 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.
authors: Ecole Polytechnique Fédérale de Lausanne (EPFL), Bâtiment SV ISREC, Station 19, CH-1015 Lausanne, Switzerland. Electronic address: Daniel.Constam@epfl.ch.
authors: Daniel B
authors: DB
authors: Constam
mesh_terms: D000818:Animals; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D043484:Proprotein Convertases / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*
chemical_list: D053779:Latent TGF-beta Binding Proteins; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D043484:Proprotein Convertases
keywords: BMP; Convertases; DPP precursor; Furin; Latency; Morphogen gradients; Nodal signaling; Proprotein processing; Protein sorting and trafficking