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.

Download full-text


Available from: Brian P Eliceiri
  • Source
    • "In addition, several studies have demonstrated that other permeabilizing agents, such as tumor necrosis factor α (TNF-α) (Angelini et al., 2006) and histamine (Andriopoulou et al., 1999), modulate AJ stability by tyrosine phosphorylation of VE-cadherin. It was shown that members of the Src kinase family phosphorylate VE-cadherin (Eliceiri et al., 1999) and Tyr685 of VE-cadherin was identified as a unique target site for c-Src in vitro (Wallez et al., 2007). Recently, it has been reported that phosphorylation at Tyr685 controls vascular permeability in vivo, while phosphorylation at Tyr731 regulates leukocyte diapedesis (Wessel et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Several vascular disorders such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension have been linked to dysfunctional BMP signaling. As vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, the role of BMPs in this process has not been investigated yet. BMP signaling is initiated by binding of ligand to and activation of BMP type I (BMPRI) and BMP type II (BMPRII) receptors. Internalization of VE-Cadherin as well as Src-kinase-dependent phosphorylation have been implicated to loosen cell-cell contacts, thereby modulating vascular permeability.Here we demonstrate that BMP6 induces hyperpermeabilization of endothelial cells by inducing internalization and Src-dependent phosphorylation of VE-Cadherin. Furthermore we show BMP-dependent physical interaction of VE-Cadherin with BMP-receptor ALK2 (BMPRI) and BMPRII resulting in stabilization of the BMP-receptor complex and thereby support of BMP6-Smad signaling.Our results give first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark in different vascular diseases, and provide the base for further investigations on BMPs as regulators of vascular integrity, both under physiological and patho-physiological conditions.
    Full-text · Article · Nov 2015 · Journal of Cell Science
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Angiogenesis is sustained by classical and non-classical proangiogenic factors (PFs) acting in tumor microenvironment and these factors are also potential targets of antiangiogenic therapies. All PFs induce the overexpression of several signaling pathways that lead to migration and proliferation of endothelial cells contributing to tumor angiogenesis and survival of cancer cells. In this review, we have analysed each PF with its specific receptor/s and we have summarized the available antiangiogenic drugs (e.g. monoclonal antibodies) targeting these PFs, some of these agents have already been approved, others are currently in development for the treatment of several human malignancies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Cancer letters
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Dec 2014 · Neural Regeneration Research
Show more