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

Oncogene. 2006 Sep 28;25(44):5969-84. doi: 10.1038/sj.onc.1209588. Epub 2006 May 8.


Elevated focal adhesion kinase (FAK) expression occurs in advanced cancers, yet a signaling role for FAK in tumor progression remains undefined. Here, we suppressed FAK activity in 4T1 breast carcinoma cells resulting in reduced FAK Y925 phosphorylation, Grb2 adaptor protein binding to FAK, and signaling to mitogen-activated protein (MAP) kinase (MAPK). Loss of a FAK-Grb2-MAPK linkage did not affect 4T1 cell proliferation or survival in culture, yet FAK inhibition reduced vascular endothelial growth factor (VEGF) expression and resulted in small avascular tumors in mice. This FAK-Grb2-MAPK linkage was essential in promoting angiogenesis as reconstitution experiments using Src-transformed FAK-null fibroblasts revealed that point mutations affecting FAK catalytic activity (R454) or Y925 phosphorylation (F925) disrupted the ability of FAK to promote MAPK- and VEGF-associated tumor growth. Notably, in both FAK-inhibited 4T1 and Src-transformed FAK-null cells, constitutively activated (CA) mitogen-activated protein kinase kinase 1 (MEK1) restored VEGF production and CA-MEK1 or added VEGF rescued tumor growth and angiogenesis. These studies provide the first biological support for Y925 FAK phosphorylation and define a novel role for FAK activity in promoting a MAPK-associated angiogenic switch during tumor progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / enzymology
  • Carcinoma / blood supply
  • Carcinoma / enzymology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cells, Cultured
  • Clone Cells
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / deficiency
  • Focal Adhesion Protein-Tyrosine Kinases / genetics
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism*
  • Humans
  • Mammary Neoplasms, Animal / blood supply
  • Mammary Neoplasms, Animal / enzymology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neovascularization, Pathologic / enzymology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / physiology
  • Signal Transduction / genetics
  • Tyrosine / metabolism*


  • Tyrosine
  • FAK-related nonkinase
  • Protein-Tyrosine Kinases
  • Focal Adhesion Protein-Tyrosine Kinases