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.
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 utilized by VEGF that includes 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 insights into c-Abl's differential functions in mediating bFGF- and VEGF-induced angiogenesis.
Yan
Wei
W
Pioneer Valley Life Sciences Institute, Baystate Medical Center/University of Massachusetts at Amherst, Springfield, MA 01107, USA.
Bentley
Brooke
B
Shao
Rong
R
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects* / Q000201:enzymology*; D003599:Cytoskeleton / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D043925:Angiogenesis Inducing Agents; D001549:Benzamides; D050505:Mutant Proteins; D010879:Piperazines; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl