OBJECTIVE: Recent evidence suggests G-protein-coupled receptor-2-interacting 
protein-1 (GIT1) overexpression in several human metastatic tumors, including 
breast, lung, and prostate. Tumor metastasis is associated with an increase in 
angiogenesis. We have showed previously that GIT1 is required for postnatal 
angiogenesis during lung development. However, the functional role of GIT1 in 
pathological angiogenesis during tumor growth is unknown.
APPROACH AND RESULTS: In the present study, we show inhibition of angiogenesis 
in matrigel implants as well as reduced tumor angiogenesis and melanoma tumor 
growth in GIT1-knockout mice. We demonstrate that this is a result of impaired 
directional migration of GIT1-depleted endothelial cells toward a vascular 
endothelial growth factor gradient. Cortactin-mediated lamellipodia formation in 
the leading edge is critical for directional migration. We observed a 
significant reduction in cortactin localization and lamellipodia formation in 
the leading edge of GIT1-depleted endothelial cells. We specifically identified 
that the Spa homology domain (aa 250-420) of GIT1 is required for GIT1-cortactin 
complex localization to the leading edge. The mechanisms involved extracellular 
signal-regulated kinases 1 and 2-mediated Cortactin-S405 phosphorylation and 
activation of Rac1/Cdc42. Finally, using gain of function studies, we show that 
a constitutively active mutant of cortactin restored directional migration of 
GIT1-depleted cells.
CONCLUSION: Our data demonstrated that a GIT1-cortactin association through 
GIT1-Spa homology domain is required for cortactin localization to the leading 
edge and is essential for endothelial cell directional migration and tumor 
angiogenesis.