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: 14.46). 01/2000; 4(6):915-24. DOI: 10.1016/S1097-2765(00)80221-X
Source: PubMed

ABSTRACT 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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Available from: Brian P Eliceiri, Aug 25, 2015
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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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    Cancer letters 07/2015; DOI:10.1016/j.canlet.2015.07.028 · 5.62 Impact Factor
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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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    ABSTRACT: The spinal cord has the ability to regenerate but the microenvironment generated after trauma reduces that capacity. An increase in Src family kinase (SFK) activity has been implicated in neuropathological conditions associated with central nervous system trauma. Therefore, we hypothesized that a decrease in SFK activation by a long-term treatment with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine (PP2), a selective SFK inhibitor, after spinal cord contusion with the New York University (NYU) impactor device would generate a permissive environment that improves axonal sprouting and/or behavioral activity. Results demonstrated that long-term blockade of SFK activation with PP2 increases locomotor activity at 7, 14, 21 and 28 days post-injury in the Basso, Beattie, and Bresnahan open field test, round and square beam crossing tests. In addition, an increase in white matter spared tissue and serotonin fiber density was observed in animals treated with PP2. However, blockade of SFK activity did not change the astrocytic response or infiltration of cells from the immune system at 28 days post-injury. Moreover, a reduced SFK activity with PP2 diminished Ephexin (a guanine nucleotide exchange factor) phosphorylation in the acute phase (4 days post-injury) after trauma. Together, these findings suggest a potential role of SFK in the regulation of spared tissue and/or axonal outgrowth that may result in functional locomotor recovery during the pathophysiology generated after spinal cord injury. Our study also points out that ephexin1 phosphorylation (activation) by SFK action may be involved in the repulsive microenvironment generated after spinal cord injury.
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    • "VEGF exerts its effects on vascular permeability through the activation of the Src family kinases, in particular c-Src (Eliceiri et al., 1999; Zachary and Gliki, 2001) and phosphoinositide 3 kinase (PI3K)/Akt-dependent phosphorylation and, hence, activation, of endothelial nitric oxide synthase (eNOS) (Ackah et al., 2005; Papapetropoulos et al., 1997). Pharmacological inhibition of Src family protein tyrosine kinases (PTKs) reduces VEGF-induced phosphorylation of AJ components and vascular permeability (Eliceiri et al., 1999; Weis et al., 2004) suggesting that there is a crucial role for c-Src in regulating EC barrier function in response to activation of growth factor receptors. By contrast, both VEGF-induced vascular leak and increases in blood flow can be blocked pharmacologically by inhibitors of NOS or its downstream targets, soluble guanylate cyclase or protein kinase G (Mayhan, 1999; Murohara et al., 1998; Papapetropoulos et al., 1997; Ziche et al., 1997). "
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