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Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors

S K Mitra1, D Mikolon, J E Molina

  • 1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Oncogene
|May 10, 2006
PubMed

Insights

Focal adhesion kinase (FAK) promotes tumor growth by enhancing angiogenesis through a MAPK signaling pathway. Inhibiting FAK reduces vascular endothelial growth factor (VEGF) and tumor vascularization, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Focal adhesion kinase (FAK) is upregulated in advanced cancers.
  • The specific signaling role of FAK in tumor progression is not fully understood.

Purpose of the Study:

  • To investigate the signaling role of FAK in tumor progression and angiogenesis.
  • To define the contribution of FAK Y925 phosphorylation to tumor growth.

Main Methods:

  • Suppressed FAK activity in 4T1 breast carcinoma cells.
  • Utilized Src-transformed FAK-null fibroblasts for reconstitution experiments.
  • Analyzed FAK Y925 phosphorylation, Grb2 binding, MAPK signaling, and VEGF expression.
  • Employed constitutively activated MEK1 to rescue VEGF production and tumor growth.

Main Results:

  • FAK inhibition reduced FAK Y925 phosphorylation, Grb2 binding, and MAPK signaling.
  • FAK inhibition decreased vascular endothelial growth factor (VEGF) expression, leading to avascular tumors in mice.
  • Mutations affecting FAK catalytic activity or Y925 phosphorylation impaired tumor growth and angiogenesis.
  • Restoring MAPK signaling or VEGF rescued tumor growth and angiogenesis.

Conclusions:

  • FAK activity, specifically Y925 phosphorylation, is essential for promoting angiogenesis via a MAPK-dependent pathway.
  • FAK plays a novel role in driving the angiogenic switch during tumor progression.
  • Targeting FAK could be a strategy to inhibit tumor angiogenesis and growth.

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