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.
Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, Wisconsin 53706, USA.
Gaoxiang
G
Ge
Delana R
DR
Hopkins
Wen-Bin
WB
Ho
Daniel S
DS
Greenspan
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