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MBC in Press, published online ahead of print March 19, 2008
Mol. Biol. Cell 10.1091/mbc.E07-10-1068

A more recent version of this article appeared on May 1, 2008
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Submitted on October 23, 2007
Revised on February 21, 2008
Accepted on February 28, 2008

Distinct Angiogenic Mediators are Required for bFGF and VEGF-induced Angiogenesis: the Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis

Wei Yan,* Brooke Bentley,* and Rong Shao*{dagger}

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

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 {beta}3 and FGF receptor, and triggered a downstream cascade including FAK, c-Abl and MAPK. This signaling pathway is different from one engaged by VEGF that utilizes integrin {beta}5, 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 insight 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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