SUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis

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.

Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma

“…In contrast, higher expression of SUMOylation (protein level) and Wnt/b-catenin, RAP1, and Notch signaling pathways (mRNA level) were observed in VEGF immune desert tumors and corresponded to the highest endothelial cell signature (t test adjusted p < 0.05) ( Figures 6B and S6E). The differential expression of VEGFR1 (FLT1) (t test adjusted p < 0.05) and multiple angiogenic-related signaling pathways may be representative of distinct mechanisms of endothelial cell recruitment and tumor vasculature formation between the two subtypes (Birdsey et al, 2015;Cao, 2013;Chrzanowska-Wodnicka, 2013;Hellströ m et al, 2007;Zhou et al, 2018;Zhu et al, 2017 Table S7). Previous reports have established a relationship between HIF-2a and MYC-induced transcription in renal carcinomas (Gordan et al, 2007a(Gordan et al, , 2008, with MYC regulation of metabolism functioning in concert with and independent of HIF-1 signaling (Gordan et al, 2007b).…”

Roles of Ubiquitination and SUMOylation in the Regulation of Angiogenesis

“…All together, these data indicate that SUMOylation inhibits VEGFR2-dependent angiogenesis ( Fig. 18.2), suggesting that the balance between the SUMOylated and non-SUMOylated VEGFR2 dictates its activation during angiogenesis (Zhou et al, 2018).…”

“…Based on the studies summarized here, it is clear that ubiquitination plays a major role in the regulation of VEGFR signalling and trafficking in angiogenesis. Interestingly, a study using a knock out mouse model of the de-SUMOylase SENP1 has described that also SUMOylation regulates the intracellular trafficking of VEGFR (Zhou et al, 2018). In particular, it has been demonstrated that SENP1 protein levels increase in vascular endothelial cells in response to ischaemia.…”

“…Further analyses have shown that SENP1 knock down in endothelial cells leads to an increase of the SUMOylation levels of VEGFR2, and to an impaired VEGFR2-dependent angiogenic signalling. Specifically, the SUMOylation of residue K1270 in VEGFR2 causes the receptor to accumulate in the Golgi compartment reducing its localization on the cell membrane (Zhou et al, 2018). Accordingly, analyses performed in diabetic mouse models, indicated that SENP1 expression was drastically reduced leading to an increase of VEGFR2 SUMOylation and inhibition of its signalling.…”

The Role of Sumoylation in the Response to Hypoxia: An Overview

“…Finally, sumoylation may also influence downstream targets of the HIF axis like the VEGF-dependent responses. The VEGF-induced angiogenic response was inhibited by SENP1 silencing, mainly because of VEGFR2 sumoylation and its subsequent accumulation at the Golgi apparatus [148]. Interestingly, products of HIF-1 gene targets, such as glucose transporters GLUT4 and GLUT1, also interact with Ubc9 and can be conjugated to SUMO [149,150].…”