SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

Huanjiao Jenny Zhou (), Zhe Xu, Zongren Wang, Haifeng Zhang, Zhen W. Zhuang, Michael Simons and Wang Min ()
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Huanjiao Jenny Zhou: Yale University School of Medicine
Zhe Xu: Yale University School of Medicine
Zongren Wang: Yale University School of Medicine
Haifeng Zhang: Yale University School of Medicine
Zhen W. Zhuang: Yale University School of Medicine
Michael Simons: Yale University School of Medicine
Wang Min: Yale University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Regulation of VEGFR2 represents an important mechanism for the control of angiogenesis. VEGFR2 activity can be regulated by post-translational modifications such as ubiquitination and acetylation. However, whether VEGFR2 can be regulated by SUMOylation has not been investigated. Here we show that endothelial-specific deletion of the SUMO endopeptidase SENP1 reduces pathological angiogenesis and tissue repair during hindlimb ischemia, and VEGF-induced angiogenesis in the cornea, retina, and ear. SENP1-deficient endothelial cells show increased SUMOylation of VEGFR2 and impaired VEGFR2 signalling. SUMOylation at lysine 1270 retains VEGFR2 in the Golgi and reduces its surface expression, attenuating VEGFR2-dependent signalling. Moreover, we find that SENP1 is downregulated and VEGFR2 hyper-SUMOylated in diabetic settings and that expression of a non-SUMOylated form of VEGFR2 rescues angiogenic defects in diabetic mice. These results show that VEGFR2 is regulated by deSUMOylation during pathological angiogenesis, and propose SENP1 as a potential therapeutic target for the treatment of diabetes-associated angiogenesis.

Date: 2018
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DOI: 10.1038/s41467-018-05812-2

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