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GDF11 forms a bone morphogenetic protein 1‐activated latent complex that can modulate nerve growth factor‐induced differentiation of PC12 cells
Author(s) -
Ge Gaoxiang,
Hopkins Delana R,
Greenspan Daniel S
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a515-a
Subject(s) - growth differentiation factor , proprotein convertase , microbiology and biotechnology , bone morphogenetic protein , cleavage (geology) , transforming growth factor , proprotein convertases , transforming growth factor beta , protein precursor , chemistry , myostatin , furin , superfamily , decapentaplegic , biology , bone morphogenetic protein 2 , transcription factor , biochemistry , gene , enzyme , in vitro , lipoprotein , paleontology , ldl receptor , enhancer , cholesterol , fracture (geology)
All transforming growth factor beta (TGF‐beta) superfamily members are synthesized as precursors with prodomain sequences that are proteolytically removed by subtilisin‐like proprotein convertases (SPCs). For most superfamily members, this is believed sufficient for activation. Exceptions are TGF‐betas 1 to 3 and growth differentiation factor 8 (GDF8), also known as myostatin, which form noncovalent, latent complexes with their SPC‐cleaved prodomains. Sequence similarities between TGF‐betas 1 to 3, myostatin, and superfamily member GDF11, also known as bone morphogenetic protein 11 (BMP11), prompted us to examine whether GDF11 might be capable of forming a latent complex with its cleaved prodomain. Here we demonstrate that GDF11 forms a noncovalent latent complex with its SPC‐cleaved prodomain and that this latent complex is activated via cleavage at a single specific site by members of the developmentally important BMP1/Tolloid family of metalloproteinases. Evidence is provided for a molecular model whereby formation and activation of this complex may play a general role in modulating neural differentiation. In particular, mutant GDF11 prodomains impervious to cleavage by BMP1/Tolloid proteinases are shown to be potent stimulators of neurodifferentiation, with potential for therapeutic applications.