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c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1

B Jiménez1, O V Volpert, F Reiher

  • 1Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.

Oncogene
|June 26, 2001
PubMed

Insights

Thrombospondin-1 (TSP-1), an angiogenesis inhibitor, activates c-Jun N-terminal kinases (JNK) via the CD36 receptor. This JNK activation is crucial for TSP-1 to block new blood vessel formation.

Area of Science:

  • Molecular biology
  • Cell biology
  • Biochemistry

Background:

  • Thrombospondin-1 (TSP-1) inhibits angiogenesis by acting on endothelial cells through the CD36 receptor.
  • TSP-1 blocks endothelial cell migration, proliferation, and morphogenesis, and inhibits neovascularization in vivo.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TSP-1 inhibits angiogenesis.
  • To determine the role of mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinases (JNK) in TSP-1-mediated anti-angiogenic signaling.

Main Methods:

  • Studied the effect of TSP-1 on MAPK and JNK activation in endothelial cells.
  • Utilized CD36 blocking antibodies and TSP-1-derived peptides to assess the role of CD36.
  • Examined corneal neovascularization in JNK-1 deficient mice.

Main Results:

  • TSP-1 did not affect MAPK activation by angiogenesis inducers.
  • TSP-1 rapidly and transiently activated JNK, dependent on CD36 engagement.
  • Inhibition of corneal neovascularization by TSP-1 was significantly reduced in JNK-1 null mice.

Conclusions:

  • TSP-1 inhibits angiogenesis through the activation of JNK, a stress-activated kinase.
  • CD36 is essential for TSP-1-induced JNK activation and subsequent anti-angiogenic effects.
  • JNK plays a critical role in TSP-1's ability to block neovascularization.

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