Parathyroid hormone–related peptide is a naturally occurring, protein kinase A–dependent angiogenesis inhibitor

Abstract

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.

Inhibition of Rac activation as a mechanism for negative regulation of actin cytoskeletal reorganization and cell motility by cAMP

“…Recently, it was reported that PTHrP (parathyroid-hormonerelated peptide) induced inhibition of Rac and cell migration in vascular endothelial cells through PKA [21], which is consistent with the present results. We have observed that PGE 2 inhibited Rac and chemotaxis through endogenous EP2 receptor in vascular smooth-muscle cells ( Figures 2E and 2F), suggesting a potential anti-atherogenic role for PGE 2 .…”

Allele-specific patterns of the mouse parathyroid hormone-related protein: influences on cell adhesion and migration

“…Cell motility is under a complex control, mediated by several signaling pathways such as those involving platelet-activating factor, integrins, phosphatidylinositol 3-kinase, and b-catenin (Boccellino et al, 2000;Mercurio et al, 2001;Muller et al, 2002). PTHrP has been recently shown to inhibit endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A (Bakre et al, 2002). However, opposite effects have been reported in malignant pituitary tumors, in which PTHrP enhances angiogenesis through capillary tube formation by endothelial cells (Akino et al, 2000).…”

Integrins: roles in cancer development and as treatment targets

“…Integrin ligation, therefore, supports signal transduction cascades that promote cell proliferation, cell survival and cell migration. In contrast, inhibition of cell integrin -ligand interaction inhibits cell migration (Kim et al, 2000a, b;Bakre et al, 2002) and proliferation and induces apoptosis (Meredith et al, 1993;Boudreau et al, 1996;Stupack et al, 2001;Bakre et al, 2002;Kim et al, 2002).…”

“…Studies from several groups showed that cell attachment is required for the survival of normal cells (Meredith et al, 1993;Stupack et al, 2001;Bakre et al, 2002). Complete loss of cell contact with the substratum (e.g., suspension culture) or adhesion to a nonspecific substratum such as poly-L-lysine induces apoptosis ('anoikis') of primary cells such as fibroblasts (Meredith et al, 1993), endothelial cells Kim et al, 2002) and epithelial cells (Frisch and Francis, 1994;Boudreau et al, 1996;Stupack et al, 2001).…”