title: Monoubiquitination of filamin B regulates vascular endothelial growth factor-mediated trafficking of histone deacetylase 7.
abstract: Nucleocytoplasmic shuttling of class IIa of histone deacetylases (HDACs) is a key mechanism that controls cell fate and animal development. We have identified the filamin B (FLNB) as a novel HDAC7-interacting protein that is required for temporal and spatial regulation of vascular endothelial growth factor (VEGF)-mediated HDAC7 cytoplasmic sequestration. This interaction occurs in the cytoplasm and requires monoubiquitination of an evolutionarily conserved lysine 1147 (K1147) in the immunoglobulin (Ig)-like repeat 10 (R10) of FLNB and the nuclear localization sequence of HDAC7. Inhibition of protein kinase C (PKC) blocks VEGF-induced ubiquitination of FLNB and its interaction with HDAC7. Small interfering RNA (siRNA) knockdown of FLNB or ubiquitin (Ub) in human primary endothelial cells blocks VEGF-mediated cytoplasmic accumulation of HDAC7, reduces VEGF-induced expression of the HDAC7 target genes Mmp-10 and Nur77, and inhibits VEGF-induced vascular permeability. Using dominant negative mutants and rescue experiments, we demonstrate the functional significance of FLNB K1147 to interfere with the ability of phorbol myristate acetate (PMA) to promote FLNB-mediated cytoplasmic accumulation of HDAC7. Taken together, our data show that VEGF and PKC promote degradation-independent protein ubiquitination of FLNB to control intracellular trafficking of HDAC7.
authors: Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, Ohio, USA.
authors: Yu-Ting
authors: YT
authors: Su
authors: Chengzhuo
authors: C
authors: Gao
authors: Yu
authors: Y
authors: Liu
authors: Shuang
authors: S
authors: Guo
authors: Anthony
authors: A
authors: Wang
authors: Benlian
authors: B
authors: Wang
authors: Hediye
authors: H
authors: Erdjument-Bromage
authors: Masaru
authors: M
authors: Miyagi
authors: Paul
authors: P
authors: Tempst
authors: Hung-Ying
authors: HY
authors: Kao
mesh_terms: D000595:Amino Acid Sequence; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D064448:Filamins; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D053506:Matrix Metalloproteinase 10 / Q000096:biosynthesis; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000096:biosynthesis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025801:Ubiquitin / Q000235:genetics; D054875:Ubiquitination; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D002227:Carbazoles; D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D007211:Indoles; D008301:Maleimides; D008840:Microfilament Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D025801:Ubiquitin; D042442:Vascular Endothelial Growth Factors; C081021:Go 6976; D011493:Protein Kinase C; D053506:Matrix Metalloproteinase 10; C543273:HDAC7 protein, human; D006655:Histone Deacetylases; D013755:Tetradecanoylphorbol Acetate
references: Nat Rev Mol Cell Biol. 2004 Apr;5(4):261-70
references: 15071551
references: J Biol Chem. 2001 Dec 14;276(50):47496-507
references: 11585834
references: J Biol Chem. 2001 May 18;276(20):17007-13
references: 11279209
references: Int J Dev Biol. 2009;53(2-3):291-301
references: 19412888
references: J Biol Chem. 2004 Aug 13;279(33):34201-8
references: 15166223
references: Nat Rev Genet. 2009 Jan;10(1):32-42
references: 19065135
references: Mol Biol Cell. 2008 Jul;19(7):3020-7
references: 18463162
references: Mol Cell Biol. 2005 Feb;25(4):1415-24
references: 15684392
references: Biol Reprod. 2010 Jan;82(1):105-11
references: 19696013
references: Pancreas. 2010 Oct;39(7):994-1001
references: 20467347
references: Trends Biochem Sci. 2006 Jul;31(7):411-9
references: 16781869
references: Cell. 2006 Jul 28;126(2):321-34
references: 16873063
references: Mol Cell Biol. 2005 Feb;25(3):1003-12
references: 15657428
references: Cell Res. 2011 Feb;21(2):365-7
references: 21079650
references: Am J Physiol Cell Physiol. 2011 Jan;300(1):C105-12
references: 20943960
references: Nat Cell Biol. 2006 Nov;8(11):1223-34
references: 17060906
references: Curr Opin Genet Dev. 2005 Jun;15(3):301-7
references: 15917206
references: J Immunol. 2011 Apr 15;186(8):4782-93
references: 21398603
references: Int J Cell Biol. 2010;2010:207420
references: 20145726
references: Biochem J. 2003 Mar 15;370(Pt 3):737-49
references: 12429021
references: Curr Opin Pharmacol. 2010 Aug;10(4):454-60
references: 20447866
references: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4562-7
references: 12682292
references: Mol Cell Biol. 2008 Sep;28(18):5658-67
references: 18625722
references: Cardiovasc Res. 2010 Jul 15;87(2):262-71
references: 20400620
references: Biochim Biophys Acta. 2010 Oct;1803(10):1186-97
references: 20621129
references: Thromb Res. 2001 Apr 15;102(2):133-42
references: 11323024
references: Cell Reprogram. 2010 Feb;12(1):43-53
references: 20132012
references: Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1782-8
references: 18617643
references: J Biol Chem. 2009 Dec 25;284(52):36395-36404
references: 19858209
references: Bioorg Med Chem. 2010 Aug 15;18(16):5950-64
references: 20650640
references: J Biol Chem. 2010 Apr 9;285(15):11219-26
references: 20133936
references: J Biol Chem. 2010 Oct 8;285(41):31418-26
references: 20675388
references: Nucleic Acids Res. 2011 Mar;39(4):1408-18
references: 20952408
references: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7738-43
references: 18509061
references: Mol Cell Biol. 2008 Feb;28(3):997-1006
references: 18039859
references: FEBS Lett. 2006 Sep 18;580(21):5096-104
references: 16956611
references: Genes Dev. 2000 Jan 1;14(1):55-66
references: 10640276