Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor
Ge, Gaoxiang | Fernández, Cecilia A. | Moses, Marsha A. | Greenspan, Daniel S.
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 TGFβ 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 [almost equal to]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 [almost equal to]17-kDa forms, whereas GH and PRL processing activity is lost in mouse embryo fibroblasts doubly null for two genes encoding BMP1-like proteinases.Show more [+] Less [-]