Nature Medicine8, 995 - 1003 (2002)
Published online: 19 August 2002; | doi:10.1038/nm753
Parathyroid hormone−related peptide is a naturally occurring, protein kinase A−dependent angiogenesis inhibitor
Manjiri M. Bakre1, Yuhong Zhu1, Hong Yin1, Doug W. Burton2, Robert Terkeltaub2, Leonard J. Deftos2
& Judith A. Varner1
1
University of California, San Diego Comprehensive Cancer Center, La Jolla, California, USA
2
Department of Medicine, University of California, and Veterans Affairs Medical Center, La Jolla, California, USA
Correspondence should be addressed to Judith A. Varner jvarner@ucsd.edu
Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone−related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone−related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone−related peptide. These studies show that parathyroid hormone−related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.
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