Selective Requirement for Src Kinases during VEGF-Induced Angiogenesis and Vascular Permeability

Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
Molecular Cell (Impact Factor: 14.02). 01/2000; 4(6):915-24. DOI: 10.1016/S1097-2765(00)80221-X
Source: PubMed


Src kinase activity was found to protect endothelial cells from apoptosis during vascular endothelial growth factor (VEGF)-, but not basic fibroblast growth factor (bFGF)-, mediated angiogenesis in chick embryos and mice. In fact, retroviral targeting of kinase-deleted Src to tumor-associated blood vessels suppressed angiogenesis and the growth of a VEGF-producing tumor. Although mice lacking individual Src family kinases (SFKs) showed normal angiogenesis, mice deficient in pp60c-src or pp62c-yes showed no VEGF-induced vascular permeability (VP), yet fyn-/- mice displayed normal VP. In contrast, inflammation-mediated VP appeared normal in Src-deficient mice. Therefore, VEGF-, but not bFGF-, mediated angiogenesis requires SFK activity in general, whereas the VP activity of VEGF specifically depends on the SFKs, Src, or Yes.

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    • "The cascade of phosphorylation of various intracellular kinases mediates each signaling pathway that, in turn, promotes gene expression via nuclear transcription factors. As a consequence, endothelial cells (ECs) migrate and proliferate finally contributing to tumor angiogenesis that facilitates survival of cancer cells [5] [6] [7] [8] [9] [10]. "
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    • "Therefore, if ephexin1 phosphorylation (activation) is decreased by PP2 (a SFK inhibitor) for 28 days, more neurons and axons can extend their neurites and growth cone bulbs, suggesting fiber sprouting at the lesion epicenter. However, we could not discard the possibility of SFK and/or ephexin1 role in synapse remodeling after SCI (Frank et al., 2009; Shi et al., 2010a, b) or regulation of vascular permeability in the injured central nervous system (Eliceiri et al., 1999; Paul et al., 2001; Akiyama et al., 2003, 2004). "
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    • "Previous studies suggested that PI3K, P38 and Raf/MEK/ERK are crucial downstream signaling targets that are involved in VEGF and FGF-induced angiogenesis [38], [39], [40]. Moreover, Src is required for the angiogenesis actions of VEGF/FGF, and VEGF/FGF-induced angiogenesis are inhibited by Src inhibitors [41], [42]. Therefore, we further investigated the roles of Src, PI3K, P38, Raf, MEK1/2, ERK1/2, Akt kinases, eNOS and HIF-1 in the angiogenesis effect of compound 10 by observing the effect of their selective pharmacological inhibitors in the zebrafish angiogenesis assay. "
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