title: Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways.
abstract: Angiogenesis is a hallmark of many diseases, including cancer, ischemic heart disease, inflammation, and others. It is well known that vascular endothelial growth factor (VEGF) is the most important angiogenic factor. Recently, we demonstrated that orphan nuclear receptor TR3 (mouse Nur77 and rat NGFI-B) plays critical roles in tumor growth and angiogenesis induced by VEGF-A in vitro and in vivo. However, the signaling pathways that mediate the expression of TR3 induced by VEGF are still not completely understood. Here we reported that 3 TR3 transcript variants (TR3-TVs) are expressed at differential levels, and regulated differentially in endothelial cells. While the expression of TR3-TV1 is relatively low, the expression of TR3-TV2 is up-regulated markedly, and the expression of TR3-TV3 is up-regulated moderately in endothelial cells induced by VEGF-A. The kinetics of the induction of these TR3-TVs is different. We also found that several signaling pathways, including calcium-PLC-PKC-PKD1 pathway, NF-κB pathway, and MAP kinase (ERK, p38, and JNK) pathways are important for VEGF-A-induced TR3-TV2 and TR3-TV3 mRNA induction. More important, we found that VEGF-A or VEGF-E, but not VEGF-B, nor placenta growth factor (PlGF), induces the phosphorylation of insulin-like growth factor-1 receptor (IGF-1R) and the interaction of VEGF receptor 2/kinase insert domain receptor (VEGFR2/KDR) with IGF-1R, which mediates the expression of TR3-TV2, but not TR3-TV3. Taking together, we demonstrate that TR3-TVs are differentially regulated by VEGF-A and identify a novel signaling pathway by which VEGF-A and VEGF-E, but neither VEGF-B, nor PlGF, induce the interaction of VEGFR2/KDR with IGF-1R, resulting in IGF-1R transactivation to induce the high level expression of TR3-TV2. Our data not only elucidate the signaling pathways by which TR3-TVs are regulated, but extend the molecular mechanism, by which VEGF-A-induced angiogenesis. These studies should permit the development of screening assays for compounds that inhibit VEGF signaling.
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Ji-nan, China;
authors.forename: Shengqiang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and Department of Hepatobiliary Surgery and Department of General Surgery, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Gengming
authors.initials: G
authors.lastname: Niu
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Ji-nan, China;
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Center for Vascular Biology Research, Division of Molecular and Vascular Biology, and hzeng@bidmc.harvard.edu.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Zeng
mesh_terms: D002118:Calcium / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C089212:protein kinase D; D017526:Receptor, IGF Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C; D002118:Calcium
keywords: IGF-1R; KDR; VEGFR2; angiogenesis; phosphorylation