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
Affiliations
Qingyun Li
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Hong Kong Branch of National Engineering Research Center of Genetic Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Chuyue Zeng
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Haizhen Liu
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Kristen Wing Yu Yung
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Chun Chen
Department of Cellular Biology, Jinan University, Guangzhou, China
Qiuling Xie
Department of Cellular Biology, Jinan University, Guangzhou, China
Yu Zhang
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Stephanie Winn Chee Wan
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Bertha Sze Wing Mak
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Jiang Xia
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Sheng Xiong
Department of Cellular Biology, Jinan University, Guangzhou, China; Hong Kong Branch of National Engineering Research Center of Genetic Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China
Jacky Chi Ki Ngo
School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Hong Kong Branch of National Engineering Research Center of Genetic Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Corresponding author
Summary: 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.
