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PNAS 104 (24): 10010-10015

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor

Gaoxiang Ge*, Cecilia A. Fernández{dagger}, Marsha A. Moses{dagger}, and Daniel S. Greenspan*,{ddagger},§

*Department of Pathology and Laboratory Medicine and {ddagger}Department of Pharmacology, University of Wisconsin, Madison, WI 53706; and {dagger}Vascular Biology Program and Department of Surgery, Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA 02115

Communicated by John D. Baxter, University of California, San Francisco, CA, May 4, 2007

Received for publication December 22, 2006.

Abstract: 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 {approx}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 {approx}17-kDa forms, whereas GH and PRL processing activity is lost in mouse embryo fibroblasts doubly null for two genes encoding BMP1-like proteinases.

Key Words: growth hormone • Tolloid • angiogenesis • phage display • mouse embryo fibroblasts

Author contributions: G.G., C.A.F., M.A.M., and D.S.G. designed research; G.G. and C.A.F. performed research; G.G., C.A.F., M.A.M., and D.S.G. analyzed data; and D.S.G. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0704179104/DC1.

§To whom correspondence should be addressed at: Department of Pathology and Laboratory Medicine, University of Wisconsin, 1300 University Avenue, Madison, WI 53706. E-mail: dsgreens{at}wisc.edu

© 2007 by The National Academy of Sciences of the USA

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