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Related Experiment Videos

Mutant Tie2 causing venous malformation signals through Shc.

Paul N Morris1, Benjamin J Dunmore, Nicholas P J Brindle

  • 1Department of Plastic, Maxillofacial and Burns Surgery, Hutt Valley Hospital, Wellington 6009, New Zealand.

Biochemical and Biophysical Research Communications
|June 8, 2006
PubMed
Summary

A mutation in Tie2 receptor tyrosine kinase causes venous malformations by activating pro-survival pathways. Targeting these pathways, involving p52 ShcA, may treat abnormal blood vessels.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Tie2 receptor tyrosine kinase is crucial for endothelial cells.
  • A specific Tie2 mutation (R849W) causes inherited venous malformations (VM).
  • Signaling pathways of mutant Tie2 in VM are currently unknown.

Purpose of the Study:

  • Identify signaling pathways activated by mutant Tie2.
  • Define phosphoproteins interacting with mutant Tie2 in endothelial cells.
  • Investigate the role of these interactions in VM pathogenesis.

Main Methods:

  • Expression of mutant Tie2 in endothelial cells.
  • Identification of interacting phosphoproteins using biochemical assays.
  • Functional analysis of identified proteins using dominant-negative constructs.

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  • Assessment of cell death and survival signaling.

    • Main Results:

    • Mutant R849W Tie2 is constitutively active in endothelial cells.
    • Mutant Tie2 recruits and phosphorylates a 52 kDa protein, identified as p52 ShcA.
    • Endothelial cells with VM-mutant Tie2 show resistance to cell death.
    • Dominant-negative ShcA expression inhibits the anti-apoptotic effect of mutant Tie2.

    Conclusions:

    • Mutant Tie2 activates pro-survival signaling through p52 ShcA.
    • This ShcA-mediated anti-apoptotic activity contributes to VM development.
    • Inhibiting this pro-survival pathway is a potential therapeutic strategy for VM regression.