Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis

Qingyun Li; Chuyue Zeng; Haizhen Liu; Kristen Wing Yu Yung; Chun Chen; Qiuling Xie; Yu Zhang; Stephanie Winn Chee Wan; Bertha Sze Wing Mak; Jiang Xia; Sheng Xiong; Jacky Chi Ki Ngo

doi:10.1016/j.isci.2021.102423

Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis

iScience. 2021 Apr 20;24(5):102423. doi: 10.1016/j.isci.2021.102423. eCollection 2021 May 21.

Authors

Qingyun Li^{1

2}, Chuyue Zeng¹, Haizhen Liu¹, Kristen Wing Yu Yung¹, Chun Chen³, Qiuling Xie³, Yu Zhang⁴, Stephanie Winn Chee Wan¹, Bertha Sze Wing Mak¹, Jiang Xia⁴, Sheng Xiong^{3

2}, Jacky Chi Ki Ngo^{1

2

5}

Affiliations

¹ School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
² Hong Kong Branch of National Engineering Research Center of Genetic Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
³ Department of Cellular Biology, Jinan University, Guangzhou, China.
⁴ Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
⁵ Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.

Abstract

Serine-arginine (SR) protein kinases (SRPKs) regulate the functions of the SR-rich splicing factors by phosphorylating multiple serines within their C-terminal arginine-serine-rich domains. Dysregulation of these phosphorylation events has been implicated in many diseases, suggesting SRPKs are potential therapeutic targets. In particular, aberrant SRPK1 expression alters the balances of proangiogenic (VEGF₁₆₅) and antiangiogenic (VEGF₁₆₅b) splicing isoforms of the key angiogenesis factor, vascular endothelial growth factor (VEGF), through the phosphorylation of prototypic SR protein SRSF1. Here, we report a protein-protein interaction (PPI) inhibitor of SRPKs, docking blocker of SRPK1 (DBS1), that specifically blocks a conserved substrate docking groove unique to SRPKs. DBS1 is a cell-permeable inhibitor that effectively inhibits the binding and phosphorylation of SRSF1 and subsequently switches VEGF splicing from the proangiogenic to the antiangiogenic isoform. Our findings thus provide a new direction for the development of SRPK inhibitors through targeting a unique PPI site to combat angiogenic diseases.

Keywords: Biochemistry; Cell Biology; Structural Biology.