Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor.
In addition to classical expression patterns in pituitary and placenta and functions in growth and reproduction, members of the small family of hormones that includes prolactin (PRL), growth hormone (GH), and placental lactogen are expressed by endothelia and have angiogenic effects. In contrast, 16- to 17-kDa proteolytic fragments of these hormones have antiangiogenic effects. Here we show that PRL and GH are bound and processed by members of the bone morphogenetic protein 1 (BMP1) subgroup of extracellular metalloproteinases, previously shown to play key roles in forming extracellular matrix and in activating certain TGFbeta superfamily members. BMP1 has previously been suggested to play roles in angiogenesis, as high throughput screens have found its mRNA to be one of those induced to highest levels in tumor-associated endothelia compared with resting endothelia. PRL and GH cleavage is shown to occur in each hormone at a single site typical of sites previously characterized in known substrates of BMP1-like proteinases, and the approximately 17-kDa PRL N-terminal fragment so produced is demonstrated to have potent antiangiogenic activity. Mouse embryo fibroblasts are shown to produce both PRL and GH and to process them to approximately 17-kDa forms, whereas GH and PRL processing activity is lost in mouse embryo fibroblasts doubly null for two genes encoding BMP1-like proteinases.
Ge
Gaoxiang
G
Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
Fernández
Cecilia A
CA
Moses
Marsha A
MA
Greenspan
Daniel S
DS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D049033:Chorioallantoic Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D017930:Genes, Reporter; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D008970:Molecular Weight; D019151:Peptide Library; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D019485:Bone Morphogenetic Proteins; D019151:Peptide Library; D011994:Recombinant Proteins; D011388:Prolactin; D013006:Growth Hormone; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1