Bone Morphogenetic Protein Clips Angiogenic Role of Prolactin

Abstract

The process of angiogenesis is critical during development and is a process that allows invasion of other tissues by cancer cells. Bone morphogenetic protein 1 (BMP1)-like proteins are proteases that help orchestrate morphogenesis. BMP1-like proteases promote deposition of extracellular matrix by cleaving precursors of structural proteins like procollagens. BMP1 also has antiangiogenic effects by releasing an antiangiogenic portion of the membrane proteoglycan perlecan. BMPs can also activate latent ligands of the transforming growth factor-β (TGF-β) superfamily. Ge et al . now report that BMP1 also appears to be an important factor in producing antiangiogenic fragments of growth hormone (GH) and prolactin (PRL). Although best known for their systemic endocrine actions, GH and PRL are also secreted locally by endothelial cells, producing paracrine or autocrine effects. The full-length hormones are angiogenic, but both can be cleaved to form N-terminal fragments that are antiangiogenic. The cleaved form of PRL is also implicated in postpartum cardiomyopathy in humans. Ge et al . fished for BMP1 substrates by screening for proteins associated with a modified form of BMP1 (which bound but did not cleave or release substrates) in a phage-display assay and found placental lactogen, a hormone related to GH and PRL. They showed that BMP1 could cleave PRL and GH to small ~17-kD fragments. They expressed truncated PRL that corresponded to the 17-kD fragment and showed that it had antiangiogenic activity in a chick chorioallantoic membrane assay and antagonized the proliferative effect of basic fibroblast growth factor on endothelial cells in culture. Mouse embryo fibroblasts lacking two genes encoding BMP1-like proteases no longer produced detectable amounts of the PRL cleavage product. The authors note that these results, along with evidence that BMP1 mRNA is highly expressed in endothelial cells associated with tumors, indicate that BMP1-like proteases may be key factors in regulation of angiogenesis. G. Ge, C. A. Fernández, M. A. Moses, D. S. Greenspan, Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor. Proc. Natl. Acad. Sci. U.S.A . 104 , 10010-10015 (2007). [Abstract] [Full Text]