Premium
Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways
Author(s) -
Zhao Shengqiang,
Zhou Lei,
Niu Gengming,
Li Yan,
Zhao Dezheng,
Zeng Huiyan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-248401
Subject(s) - orphan receptor , neuron derived orphan receptor 1 , differential (mechanical device) , nuclear receptor , computational biology , signal transduction , biology , genetics , gene , transcription factor , physics , thermodynamics
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/ KDRwith 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.—Zhao, S., Zhou, L., Niu, G., Li, Y., Zhao, D., Zeng, H., Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways. FASEB J. 28, 4524–4533 (2014). www.fasebj.org