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VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling.

Publication ,  Journal Article
Findley, CM; Cudmore, MJ; Ahmed, A; Kontos, CD
Published in: Arterioscler Thromb Vasc Biol
December 2007

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. METHODS AND 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.

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Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

December 2007

Volume

27

Issue

12

Start / End Page

2619 / 2626

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Vascular Endothelial Growth Factor A
  • Transfection
  • Tetradecanoylphorbol Acetate
  • Signal Transduction
  • Receptor, TIE-2
  • Pyridines
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Phosphorylation
 

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Findley, C. M., Cudmore, M. J., Ahmed, A., & Kontos, C. D. (2007). VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol, 27(12), 2619–2626. https://doi.org/10.1161/ATVBAHA.107.150482
Findley, Clarence M., Melissa J. Cudmore, Asif Ahmed, and Christopher D. Kontos. “VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling.Arterioscler Thromb Vasc Biol 27, no. 12 (December 2007): 2619–26. https://doi.org/10.1161/ATVBAHA.107.150482.
Findley CM, Cudmore MJ, Ahmed A, Kontos CD. VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2619–26.
Findley, Clarence M., et al. “VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling.Arterioscler Thromb Vasc Biol, vol. 27, no. 12, Dec. 2007, pp. 2619–26. Pubmed, doi:10.1161/ATVBAHA.107.150482.
Findley CM, Cudmore MJ, Ahmed A, Kontos CD. VEGF induces Tie2 shedding via a phosphoinositide 3-kinase/Akt dependent pathway to modulate Tie2 signaling. Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2619–2626.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

December 2007

Volume

27

Issue

12

Start / End Page

2619 / 2626

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Vascular Endothelial Growth Factor A
  • Transfection
  • Tetradecanoylphorbol Acetate
  • Signal Transduction
  • Receptor, TIE-2
  • Pyridines
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase Inhibitors
  • Phosphorylation