title: Requirement of novel amino acid fragments of orphan nuclear receptor TR3/Nur77 for its functions in angiogenesis.
abstract: Pathological angiogenesis is a hallmark of many diseases. We demonstrated that TR3/Nur77 is an excellent target for pro-angiogenesis and anti-angiogenesis therapies. Here, we report that TR3 transcriptionally regulates endothelial cell migration, permeability and the formation of actin stress fibers that is independent of RhoA GTPase. 1) Amino acid residues 344-GRR-346 and de-phosphorylation of amino acid residue serine 351 in the DNA binding domain, and 2) phosphorylation of amino acid residues in the 41-61 amino acid fragment of the transactivation domain, of TR3 are required for its induction of the formation of actin stress fibers, cell proliferation, migration and permeability. The 41-61 amino acid fragment contains one of the three potential protein interaction motifs in the transactivation domain of TR3, predicted by computational modeling and analysis. These studies further our understanding of the molecular mechanism, by which TR3 regulates angiogenesis, identify novel therapeutic targeted sites of TR3, and set the foundation for the development of high-throughput screening assays to identify compounds targeting TR3/Nur77 for pro-angiogenesis and anti-angiogenesis therapies.
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Ji-nan, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Pierre M
authors.initials: PM
authors.lastname: Bourbon
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Grant
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Department of Medical Oncology and Radiation Oncology, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, PR China.
authors.forename: Taiyang
authors.initials: T
authors.lastname: Ye
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.|Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research and Division of Molecular and Vascular Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
mesh_terms: D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000737:chemistry; D001665:Binding Sites; D002463:Cell Membrane Permeability; D002465:Cell Movement; D049109:Cell Proliferation; D003198:Computer Simulation; D042783:Endothelial Cells; D057166:High-Throughput Screening Assays; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D009389:Neovascularization, Pathologic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000596:Amino Acids; D020533:Angiogenesis Inhibitors; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D042461:Vascular Endothelial Growth Factor A; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein
keywords: actin stress fibers; migration; permeability; proliferation; protein binding site