Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

J Clin Invest. 2012 Jun;122(6):1991-2005. doi: 10.1172/JCI58832. Epub 2012 May 15.

Abstract

Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism*
  • Animals
  • Down-Regulation*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Integrins / genetics
  • Integrins / metabolism*
  • Male
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Phosphorylation / genetics
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, TIE-2
  • Signal Transduction*
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Angiopoietin-2
  • Integrins
  • Neoplasm Proteins
  • Neuropeptides
  • RAC1 protein, human
  • Rac1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-2
  • Tek protein, mouse
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Ptk2 protein, mouse
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein