title: You're going to need a bigger (glass bottom) boat.
abstract: Signaling molecules of the transforming growth factor (TGF)-β family are generated from proprotein precursors containing prodomain sequences that are typically removed to allow signaling by the mature ligands. A form of a TGF-β family ligand that remains covalently attached to its prodomain but retains signaling activity has been identified. Glass bottom boat (Gbb), a Drosophila homolog of the bone morphogenetic protein 5/6/7/8 subfamily, is active as a carboxyl-terminal fragment of the proprotein (Gbb15) that is generated by a conventional processing event common to TGF-β ligands. Unexpectedly, a larger form (Gbb38) produced by processing at a newly identified furin site in the prodomain is also secreted and active. Contrary to the present paradigm in which TGF-β ligands require dissociation of the entire prodomain for activity, Gbb38 is active in cell culture and in vivo without additional processing at conventional sites. The large form can restore the viability of gbb mutant animals but has distinct signaling properties compared with the conventional form. Production of multiple functional ligands from one proprotein is a potential mechanism to fine-tune TGF-β signaling outputs. Mutations in TGF-β family members have been linked to human diseases, several of which affect potential furin cleavage sites in prodomains. However, given the diversity of potential furin processing sites and prodomain functions, direct experimentation will be required to determine whether production of active jumbo ligands is a general feature of TGF-β superfamily members.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Aidan J
authors.initials: AJ
authors.lastname: Peterson
authors.forename: Michael B
authors.initials: MB
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D045683:Furin / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D029721:Drosophila Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; C089440:gbb protein, Drosophila; D045683:Furin