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The TIE Receptor Family

  • Pipsa Saharinen
  • Michael Jeltsch
  • Mayte M. Santoyo
  • Veli-Matti Leppänen
  • Kari AlitaloEmail author

Abstract

The endothelial TIE1 and TIE2 receptor tyrosine kinases form a distinct subfamily characterized by their unique extracellular domains. Together with the angiopoietin growth factors (ANGPT1, ANGPT2, ANGPT4, also abbreviated as ANG), the TIE receptors form an endothelial specific signaling pathway with important functions in the regulation of lymphatic and cardiovascular development and vascular homeostasis. Angiopoietins exist in multimeric forms that activate the TIE receptors via unique mechanism. In endothelial cell–cell contacts, angiopoietins induce the formation of homomeric in trans TIE receptor complexes extending across the cell junctions, whereas matrix-bound angiopoietin-1 (ANG1) activates the TIE receptors in a cis configuration. In comparison to the vascular endothelial growth factor receptors, the TIE receptors undergo little ubiquitin-mediated degradation after activation, whereas TIE2 signaling is negatively regulated by the vascular endothelial protein tyrosine phosphatase, VE-PTP. ANG1 activation of TIE2 supports vascular stabilization, whereas angiopoietin-2 (ANG2), a context-dependent weak TIE2 agonist/antagonist, promotes pathological tumor angiogenesis, vascular permeability, and inflammation. Recently, ANG2 has been found to mediate some of its vascular destabilizing and angiogenic functions via integrin signalling. The circulating levels of ANG2 are increased in cancer, and in several human diseases associated with inflammation and vascular leak, for example, in sepsis. Blocking of ANG2 has emerged as a potential novel therapeutic strategy for these diseases. In addition, preclinical results demonstrate that genetic TIE1 deletion in mice inhibits the vascularization and growth of tumor isografts and protects from atherosclerosis, with little effect on normal vascular homeostasis in adult mice. The ability of the ANG-TIE pathway to control vessel stability and angiogenesis makes it an interesting vascular target for the treatment of the various diseases.

Keywords

TIE1 TIE2 Angiopoietin ANGPT ANG Endothelial cell Vascular dysfunction Lymphatic vessel Neovascularization 

Notes

Acknowledgements

This work has received funding from the European Research Council (ERC-2010-AdG-26884), the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007–2013/ under REA grant agreement n° 317250, the Leducq Foundation (grant n:o 11CVD03), the Sigrid Juselius Foundation, the Finnish Cancer Organizations, the Worldwide Cancer Research (12-0181) and the Academy of Finland Centre of Excellence Program 2014–2019 (n:o 271845).

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Pipsa Saharinen
    • 1
    • 2
    • 3
  • Michael Jeltsch
    • 1
    • 2
    • 4
  • Mayte M. Santoyo
    • 1
  • Veli-Matti Leppänen
    • 1
  • Kari Alitalo
    • 1
    • 2
  1. 1.Wihuri Research InstituteBiomedicum HelsinkiHelsinkiFinland
  2. 2.Translational Cancer Biology Program, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of VirologyUniversity of HelsinkiHelsinkiFinland
  4. 4.Department of BiomedicineUniversity of HelsinkiHelsinkiFinland

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