title: ERK3 promotes endothelial cell functions by upregulating SRC-3/SP1-mediated VEGFR2 expression.
abstract: Despite a regain of interest recently in ERK3 kinase signaling, the molecular regulations of both ERK3 gene expression and protein kinase activity are still largely unknown. While it is shown that disruption of ERK3 gene causes neonatal lethality, cell type-specific functions of ERK3 signaling remain to be explored. In this study, we report that ERK3 gene expression is upregulated by cytokines through c-Jun in endothelial cells; c-Jun binds to the ERK3 gene and regulates its transcription. We further reveal a new role for ERK3 in regulating endothelial cell migration, proliferation and tube formation by upregulating SRC-3/SP-1-mediated VEGFR2 expression. The underlying molecular mechanism involves ERK3-stimulated formation of a transcriptional complex involving coactivator SRC-3, transcription factor SP-1 and the secondary coactivator CBP. Taken together, our study identified a molecular regulatory mechanism of ERK3 gene expression and revealed a previously unknown role of ERK3 in regulating endothelial cell functions.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ka
authors.initials: K
authors.lastname: Bian
authors.forename: Sreeram
authors.initials: S
authors.lastname: Vallabhaneni
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Ray-Chang
authors.initials: RC
authors.lastname: Wu
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Weiwen
authors.initials: W
authors.lastname: Long
mesh_terms: D001665:Binding Sites; D050882:CREB-Binding Protein / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D056921:Nuclear Receptor Coactivator 3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D048053:Mitogen-Activated Protein Kinase 6