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Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis
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 poten...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102418/ https://www.ncbi.nlm.nih.gov/pubmed/33997701 http://dx.doi.org/10.1016/j.isci.2021.102423 |
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author | Li, Qingyun Zeng, Chuyue Liu, Haizhen Yung, Kristen Wing Yu Chen, Chun Xie, Qiuling Zhang, Yu Wan, Stephanie Winn Chee Mak, Bertha Sze Wing Xia, Jiang Xiong, Sheng Ngo, Jacky Chi Ki |
author_facet | Li, Qingyun Zeng, Chuyue Liu, Haizhen Yung, Kristen Wing Yu Chen, Chun Xie, Qiuling Zhang, Yu Wan, Stephanie Winn Chee Mak, Bertha Sze Wing Xia, Jiang Xiong, Sheng Ngo, Jacky Chi Ki |
author_sort | Li, Qingyun |
collection | PubMed |
description | 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 (VEGF(165)) and antiangiogenic (VEGF(165)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. |
format | Online Article Text |
id | pubmed-8102418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-81024182021-05-14 Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis Li, Qingyun Zeng, Chuyue Liu, Haizhen Yung, Kristen Wing Yu Chen, Chun Xie, Qiuling Zhang, Yu Wan, Stephanie Winn Chee Mak, Bertha Sze Wing Xia, Jiang Xiong, Sheng Ngo, Jacky Chi Ki iScience Article 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 (VEGF(165)) and antiangiogenic (VEGF(165)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. Elsevier 2021-04-20 /pmc/articles/PMC8102418/ /pubmed/33997701 http://dx.doi.org/10.1016/j.isci.2021.102423 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Li, Qingyun Zeng, Chuyue Liu, Haizhen Yung, Kristen Wing Yu Chen, Chun Xie, Qiuling Zhang, Yu Wan, Stephanie Winn Chee Mak, Bertha Sze Wing Xia, Jiang Xiong, Sheng Ngo, Jacky Chi Ki Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title | Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title_full | Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title_fullStr | Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title_full_unstemmed | Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title_short | Protein-Protein Interaction Inhibitor of SRPKs Alters the Splicing Isoforms of VEGF and Inhibits Angiogenesis |
title_sort | protein-protein interaction inhibitor of srpks alters the splicing isoforms of vegf and inhibits angiogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102418/ https://www.ncbi.nlm.nih.gov/pubmed/33997701 http://dx.doi.org/10.1016/j.isci.2021.102423 |
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