Yan Wei, Bentley Brooke, Shao Rong
Pioneer Valley Life Sciences Institute, Baystate Medical Center/University of Massachusetts at Amherst, Springfield, MA 01107, USA.
Mol Biol Cell. 2008 May;19(5):2278-88. doi: 10.1091/mbc.e07-10-1068. Epub 2008 Mar 19.
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.
血管生成因子碱性成纤维细胞生长因子（bFGF）和血管内皮生长因子（VEGF）在肿瘤血管生成中所涉及的信号通路尚未完全明确。当前研究确定细胞质酪氨酸激酶c-Abl是在微血管内皮细胞中差异介导bFGF和VEGF诱导的血管生成的关键因子。c-Abl激酶抑制剂STI571仅抑制bFGF诱导的血管生成，而不抑制VEGF诱导的血管生成。bFGF诱导整合素β3与FGF受体之间的膜受体协作，并触发包括黏着斑激酶（FAK）、c-Abl和丝裂原活化蛋白激酶（MAPK）在内的下游级联反应。该信号通路不同于VEGF所利用的信号通路，后者包括整合素β5、VEGF受体-2、Src、FAK和MAPK。野生型c-Abl的异位表达使血管生成对bFGF的反应敏感，但激酶失活突变体c-Abl消除了这种活性。此外，野生型c-Abl在基质胶植入和肿瘤异种移植模型中均增强了血管生成。这些数据为c-Abl在介导bFGF和VEGF诱导的血管生成中的差异功能提供了新的见解。
