title: Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis.
abstract: Angiogenesis is stimulated by vascular endothelial growth factor (VEGF) and antagonized by type 1 interferons, including IFN-α/β. On engaging their respective receptors (VEGFR2 and IFNAR), both stimuli activate protein kinase D2 (PKD2) and type 1 IFNs require PKD2 activation and recruitment to IFNAR1 to promote the phosphorylation-dependent ubiquitination, down-regulation, and degradation of the cognate receptor chain, IFNAR1. Data reveal that PKD2 activity is dispensable for VEGF-stimulated down-regulation of VEGFR2. Remarkably, VEGF treatment promotes the recruitment of PKD2 to IFNAR1 as well as ensuing phosphorylation, ubiquitination, and degradation of IFNAR1. In cells exposed to VEGF, phosphorylation-dependent degradation of IFNAR1 leads to an inhibition of type 1 IFN signaling and is required for efficient VEGF-stimulated angiogenesis. Importance of this mechanism for proangiogenic or antiangiogenic responses in cells exposed to counteracting stimuli and the potential medical significance of this regulation are discussed.
authors.affiliation: Department of Animal Biology and Mari Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D054875:Ubiquitination; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C507964:IFNAR1 protein, human; D007370:Interferon Type I; D016898:Interferon-alpha; D000091283:Protein Kinase D2; D042461:Vascular Endothelial Growth Factor A; D053633:Receptor, Interferon alpha-beta; D011494:Protein Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2