VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling.
OBJECTIVE
Tie2 and its ligands, the angiopoietins (Ang), are required for embryonic and postnatal angiogenesis. Previous studies have demonstrated that Tie2 is proteolytically cleaved, resulting in the production of a 75-kDa soluble receptor fragment (sTie2). We investigated mechanisms responsible for Tie2 shedding and its effects on Tie2 signaling and endothelial cellular responses.


RESULTS
sTie2 bound both Ang1 and Ang2 and inhibited angiopoietin-mediated Tie2 phosphorylation and antiapoptosis. In human umbilical vein endothelial cells, Tie2 shedding was both constitutive and induced by treatment with PMA or vascular endothelial growth factor (VEGF). Constitutive and VEGF-inducible Tie2 shedding were mediated by PI3K/Akt and p38 MAPK. Tie2 shedding was blocked by pharmacological inhibitors of either PI3K or Akt as well as by overexpression of the lipid phosphatase PTEN. In contrast, sTie2 shedding was enhanced by overexpression of either dominant negative PTEN, which increased Akt phosphorylation, or constitutively active, myristoylated Akt.


CONCLUSIONS
These findings demonstrate that VEGF regulates angiopoietin-Tie2 signaling by inducing proteolytic cleavage and shedding of Tie2 via a novel PI3K/Akt-dependent pathway. These results suggest a previously unrecognized mechanism by which VEGF may inhibit vascular stabilization to promote angiogenesis and vascular remodeling.
Findley
Clarence M
CM
Department of Pharmacology and Cancer Biology, Duke University Medical Center and the Duke University School of Medicine, Durham, NC, Durham, NC 27710, USA.
Cudmore
Melissa J
MJ
Ahmed
Asif
A
Kontos
Christopher D
CD
D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D002867:Chromones; D004151:Dipeptides; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D010446:Peptide Fragments; D010447:Peptide Hydrolases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D042787:Receptor, TIE-2; D013755:Tetradecanoylphorbol Acetate; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093642:SB 203580