Phosphorylation of Akt and ERK1-2 Is Required for VEGF-A-VEGFR2-Induced Proliferation and Migration of Lymphatic EndotheliumReport as inadecuate




Phosphorylation of Akt and ERK1-2 Is Required for VEGF-A-VEGFR2-Induced Proliferation and Migration of Lymphatic Endothelium - Download this document for free, or read online. Document in PDF available to download.

There is growing evidence that vascular endothelial growth factor-A VEGF-A, a ligand of the receptor tyrosine kinases VEGFR1 and VEGFR2, promotes lymphangiogenesis. However, the underlying mechanisms by which VEGF-A induces the growth of lymphatic vessels remain poorly defined. Here we report that VEGFR2, not VEGFR1, is the primary receptor regulating VEGF-A-induced lymphangiogenesis. We show that specific inhibition of VEGF-A-VEGFR2 signaling with the fully human monoclonal antibody r84 significantly inhibits lymphangiogenesis in MDA-MB-231 tumors. In vitro experiments with primary human dermal lymphatic endothelial cells LECs demonstrate that blocking VEGF-A activation of VEGFR2, not VEGFR1, significantly inhibits VEGF-A-induced proliferation and migration of LECs. We show that VEGF-A stimulation of LECs leads to the phosphorylation of VEGFR2 Tyr 951, 1054, 1059, 1175, and 1214 which subsequently triggers PKC dependent phosphorylation of ERK1-2 and PI3-K dependent phosphorylation of Akt. Additionally, we demonstrate that inhibitors that suppress the phosphorylation of ERK1-2 and Akt significantly block VEGF-A- induced proliferation and migration of LECs. Together, these results shed light on the mechanisms regulating VEGF-A-induced proliferation and migration of LECs, reveal that VEGFR2 is the primary signaling VEGF-A receptor on lymphatic endothelium, and suggest that therapeutic agents targeting the VEGF-A-VEGFR2 axis could be useful in blocking the pathological formation of lymphatic vessels.



Author: Michael T. Dellinger, Rolf A. Brekken

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents