Parathyroid hormone-related peptide is a naturally occurring, protein kinase A-dependent angiogenesis inhibitor.
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.
University of California, San Diego Comprehensive Cancer Center, La Jolla, California, USA.
Manjiri M
MM
Bakre
Yuhong
Y
Zhu
Hong
H
Yin
Doug W
DW
Burton
Robert
R
Terkeltaub
Leonard J
LJ
Deftos
Judith A
JA
Varner
D020533:Angiogenesis Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D015197:Carcinogenicity Tests; D002465:Cell Movement; D002642:Chick Embryo; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004730:Endothelium, Vascular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D018014:Gene Transfer Techniques; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein; D010449:Peptide Mapping; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D013449:Sulfonamides; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D013449:Sulfonamides; D016222:Fibroblast Growth Factor 2; D017868:Cyclic AMP-Dependent Protein Kinases; D020744:rac GTP-Binding Proteins; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide