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Vol. 19, Issue 5, 2278-2288, May 2008

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Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor– and Vascular Endothelial Growth Factor–induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis

Wei Yan^*, Brooke Bentley^*, and Rong Shao^*,

*Pioneer Valley Life Sciences Institute, Baystate Medical Center/University of Massachusetts at Amherst, Springfield, MA 01107; and Program of Molecular and Cellular Biology and Department of Veterinary and Animal Science, University of Massachusetts, Amherst, MA 01003

Submitted October 23, 2007; Revised February 21, 2008; Accepted February 28, 2008
Monitoring Editor: Mark Ginsberg

Signaling pathways engaged by angiogenic factors bFGF and VEGF in tumor angiogenesis are not fully understood. The current study identifies cytoplasmic tyrosine kinase c-Abl as a key factor differentially mediating bFGF- and VEGF-induced angiogenesis in microvascular endothelial cells. STI571, a c-Abl kinase inhibitor, only inhibited bFGF- but not VEGF-induced angiogenesis. bFGF induced membrane receptor cooperation between integrin β₃ and FGF receptor, and triggered a downstream cascade including FAK, c-Abl, and MAPK. This signaling pathway is different from one utilized by VEGF that includes integrin β₅, VEGF receptor-2, Src, FAK, and MAPK. Ectopic expression of wild-type c-Abl sensitized angiogenic response to bFGF, but kinase dead mutant c-Abl abolished this activity. Furthermore, the wild-type c-Abl enhanced angiogenesis in both Matrigel implantation and tumor xenograft models. These data provide novel insights into c-Abl's differential functions in mediating bFGF- and VEGF-induced angiogenesis.

Address correspondence to: Rong Shao (rong.shao{at}bhs.org)

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