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.


Available from: Shusheng Wang
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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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    BioMed Research International 05/2014; 2014:756078. DOI:10.1155/2014/756078 · 1.58 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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    • "They were later shown to be essential for the fission of vesicles from the TGN that travel to the basolateral plasma membrane (Liljedahl et al., 2001; Yeaman et al., 2004). Many articles have recently shown that PKDs are also involved in other cellular processes, including axonal elongation, proliferation , adhesion, migration, apoptosis, and cell survival, as well as higher order biological processes such as cardiac hypertrophy, angiogenesis, immune responses, and insulin secretion (Bisbal et al., 2008; Rozengurt et al., 2005; Carnegie et al., 2008; Fielitz et al., 2008; Ha et al., 2008; Wang et al., 2008; Ivison et al., 2007; Ren et al., 2009; Yin et al., 2008; Sumara et al., 2009; Gehart et al., 2012 ). Most of these studies used cell culture model systems. "
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    ABSTRACT: Protein Kinase D (PKD) 1, 2, and 3 are members of the PKD family. PKDs influence many cellular processes, including cell polarity, structure of the Golgi, polarized transport from the Golgi to the basolateral plasma membrane and actin polymerization. However, the role of the PKD family in cell polarity has not yet been elucidated in vivo. Here, we show that KO mice displayed similar localization of the apical and basolateral proteins, transport of VSV-G and a GPI-anchored protein, and similar localization of actin filaments. As DKO mice were embryonic lethal, we generated MEFs that lacked all PKD isoforms from the PKD1 and PKD2 double floxed mice using Cre recombinase and PKD3 siRNA. We observed a similar localization of various organelles, a similar time course in the transport of VSV-G and a GPI-anchored protein, and a similar distribution of F-actin in the PKD-null MEFs. Collectively, our results demonstrate that the complete deletion of PKDs does not affect the transport of VSV-G or a GPI-anchored protein, and the distribution of F-actin. However, simultaneous deletion of PKD1 and PKD2 affect embryonic development, demonstrating their functional redundancy during development.
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