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Molecular Endocrinology 13 (5): 692-704
Copyright © 1999 by The Endocrine Society

16K Human Prolactin Inhibits Vascular Endothelial Growth Factor-Induced Activation of Ras in Capillary Endothelial Cells

Gisela D’Angelo1,2, Jean-François Martini1, Taroh Iiri3, Wendy J. Fantl, Joseph Martial and Richard I. Weiner

Reproductive Endocrinology Center Department of Obstetrics, Gynecology and Reproductive Sciences University of California School of Medicine San Francisco, California 94143 Departments of Cellular and Molecular Pharmacology and Medicine (T.I.) University of California San Francisco, California 94143
Technologies Research and Development (W.J.F.) Chiron Corp. Emeryville, California 94608
Laboratoire de Biologie Moléculaire et de Génie Génétique (J.M.) Université de Liège B-4000 Sart Tilman, Belgium

Signaling pathways mediating the antiangiogenic action of 16K human (h)PRL include inhibition of vascular endothelial growth factor (VEGF)-induced activation of the mitogen-activated protein kinases (MAPK). To determine at which step 16K hPRL acts to inhibit VEGF-induced MAPK activation, we assessed more proximal events in the signaling cascade. 16K hPRL treatment blocked VEGF-induced Raf-1 activation as well as its translocation to the plasma membrane. 16K hPRL indirectly increased cAMP levels; however, the blockade of Raf-1 activation was not dependent on the stimulation of cAMP-dependent protein kinase (PKA), but rather on the inhibition of the GTP-bound Ras. The VEGF-induced tyrosine phosphorylation of the VEGF receptor, Flk-1, and its association with the Shc/Grb2/Ras-GAP (guanosine triphosphatase-activating protein) complex were unaffected by 16K hPRL treatment. In contrast, 16K hPRL prevented the VEGF-induced phosphorylation and dissociation of Sos from Grb2 at 5 min, consistent with inhibition by 16K hPRL of the MEK/MAPK feedback on Sos. The inhibition of Ras activation was paralleled by the increased phosphorylation of 120 kDa proteins comigrating with Ras-GAP. Taken together, these findings show that 16K hPRL inhibits the VEGF-induced Ras activation; this antagonism represents a novel and potentially important mechanism for the control of angiogenesis.




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