16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells.
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.
Mesh Terms:
Biological Transport, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Activation, GRB10 Adaptor Protein, GTPase-Activating Proteins, Genes, ras, Humans, Lymphokines, Membrane Proteins, Peptide Fragments, Prolactin, Proteins, Proto-Oncogene Proteins c-raf, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, Son of Sevenless Proteins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, ras GTPase-Activating Proteins, ras Proteins
Biological Transport, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Endothelial Growth Factors, Endothelium, Vascular, Enzyme Activation, GRB10 Adaptor Protein, GTPase-Activating Proteins, Genes, ras, Humans, Lymphokines, Membrane Proteins, Peptide Fragments, Prolactin, Proteins, Proto-Oncogene Proteins c-raf, Receptor Protein-Tyrosine Kinases, Receptors, Growth Factor, Receptors, Vascular Endothelial Growth Factor, Signal Transduction, Son of Sevenless Proteins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, ras GTPase-Activating Proteins, ras Proteins
Mol. Endocrinol.
Date: May. 01, 1999
PubMed ID: 10319320
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