GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells.
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.
Ge
Gaoxiang
G
Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Hopkins
Delana R
DR
Ho
Wen-Bin
WB
Greenspan
Daniel S
DS
D000595:Amino Acid Sequence; D000818:Animals; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D055412:Growth Differentiation Factors; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D016716:PC12 Cells; D010455:Peptides / Q000378:metabolism; D043484:Proprotein Convertases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D010455:Peptides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020932:Nerve Growth Factor; D043484:Proprotein Convertases; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; C525708:Bmp1 protein, rat; D055395:Bone Morphogenetic Protein 1