Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7. PNAS

Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9148.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2008; 105(22):7738-43. DOI: 10.1073/pnas.0802857105
Source: PubMed


VEGF has been shown to regulate endothelial cell (EC) proliferation and migration. However, the nuclear mediators of the actions of VEGF in ECs have not been fully defined. We show that VEGF induces the phosphorylation of three conserved serine residues in histone deacetylase 7 (HDAC7) via protein kinase D, which promotes nuclear export of HDAC7 and activation of VEGF-responsive genes in ECs. Expression of a signal-resistant HDAC7 mutant protein in ECs inhibits proliferation and migration in response to VEGF. These results demonstrate that phosphorylation of HDAC7 serves as a molecular switch to mediate VEGF signaling and endothelial function.

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Available from: Shusheng Wang, Oct 04, 2015
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    • "The role of VEGF as major inducer of angiogenesis is well recognized [66]. VEGF induces expression of α1β1 and α2β1 integrins in microvascular endothelial cells [67], endothelial cell migration, and proliferation [68, 69]. VEGF is not stored intracellularly but it bounds the cell surface or ECM and various MMPs [70] and PA [71] can generate diffusible, non-heparin-binding fragments. "
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    ABSTRACT: Angiogenesis is a multistep process driven by a wide range of positive and negative regulatory factors. Extracellular matrix (ECM) plays a crucial role in the regulation of this process. The degradation of ECM, occurring in response to an angiogenic stimulus, leads to degradation or partial modification of matrix molecules, release of soluble factors, and exposure of cryptic sites with pro- and/or antiangiogenic activity. ECM molecules and fragments, resulting from proteolysis, can also act directly as inflammatory stimuli, and this can explain the exacerbated angiogenesis that drives and maintains several inflammatory diseases. In this review we have summarized some of the more recent literature data concerning the molecular control of ECM in angiogenesis in both physiological and pathological conditions.
    BioMed Research International 05/2014; 2014:756078. DOI:10.1155/2014/756078 · 3.17 Impact Factor
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    • "Increasing evidence indicates the contribution of class IIa KDACs, such as HDAC5, HDAC6, and HDAC7, to the angiogenic function of endothelial cells (Wang et al., 2008; Urbich et al., 2009; Kaluza et al., 2011). In particular, HDAC6 has already been shown to promote angiogenesis in vitro and in vivo by deacetylating the cytoplasmic actin-remodeling protein cortactin in endothelial cells, thereby regulating endothelial cell migration and sprouting (Kaluza et al., 2011). "
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    ABSTRACT: The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6. We demonstrate that VEGFR2 acetylation essentially regulates receptor phosphorylation. In particular, VEGFR2 acetylation significantly alters the kinetics of receptor phosphorylation after ligand binding, allowing receptor phosphorylation and intracellular signaling upon prolonged stimulation with VEGF. Molecular dynamics simulations indicate that acetylation of the lysine in the activation loop contributes to the transition to an open active state, in which tyrosine phosphorylation is favored by better exposure of the kinase target residues. These findings indicate that post-translational modification by acetylation is a critical mechanism that directly affects VEGFR2 function.
    Journal of Molecular Cell Biology 03/2014; 6(2). DOI:10.1093/jmcb/mju010 · 6.77 Impact Factor
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    • "The expression of HIF-1α can be reduced via HDAC1 by upregulating p53 and the Von Hippel–Lindau protein, through which the expression of VEGF is also inhibited [67]. HDAC7 associates with HIF-1α to increase HIF-1α’s transactivation ability [68], but VEGF induces the nuclear exit of HDAC7 to activate proangiogenic gene expression [69]. The HIF-1-directed hypoxic response can be regulated by histone methylation as well [70]. "
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    ABSTRACT: Epigenetics has become an increasingly important area of biomedical research. Increasing evidence shows that epigenetic alterations influence common pathologic responses including inflammation, ischemia, neoplasia, aging, and neurodegeneration. Importantly, epigenetic mechanisms may have a pathogenic role in many complex eye diseases such as corneal dystrophy, cataract, glaucoma, diabetic retinopathy, ocular neoplasia, uveitis, and age-related macular degeneration. The emerging emphasis on epigenetic mechanisms in studies of eye disease may provide new insights into the pathogenesis of complex eye diseases and aid in the development of novel treatments for these diseases.
    Molecular vision 03/2013; 19:665-74. · 1.99 Impact Factor
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