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
Abstract
b) 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.