Vascular endothelial growth factor–induced elimination of the type 1 interferon receptor is required for efficient angiogenesis

H Zheng, J Qian, CJ Carbone, NA Leu… - Blood, The Journal …, 2011 - ashpublications.org
H Zheng, J Qian, CJ Carbone, NA Leu, DP Baker, SY Fuchs
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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