Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability
Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C(CDH1)), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. How...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882653/ https://www.ncbi.nlm.nih.gov/pubmed/36711754 http://dx.doi.org/10.21203/rs.3.rs-2447544/v1 |
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author | Ke, Shizhong Dang, Fabin Wang, Lin Chen, Jia-Yun Naik, Mandar T. Thavamani, Abhishek Liu, Yansheng Li, Wenxue Kim, Nami Naik, Nandita M. Sui, Huaxiu Tang, Wei Qiu, Chenxi Koikawa, Kazuhiro Batalini, Felipe Wang, Xiaodong Clohessy, John G. Heng, Yujing Jan Lahav, Galit Gray, Nathanael S. Zho, Xiao Zhen Wei, Wenyi Wulf, Gerburg M. Lu, Kun Ping |
author_facet | Ke, Shizhong Dang, Fabin Wang, Lin Chen, Jia-Yun Naik, Mandar T. Thavamani, Abhishek Liu, Yansheng Li, Wenxue Kim, Nami Naik, Nandita M. Sui, Huaxiu Tang, Wei Qiu, Chenxi Koikawa, Kazuhiro Batalini, Felipe Wang, Xiaodong Clohessy, John G. Heng, Yujing Jan Lahav, Galit Gray, Nathanael S. Zho, Xiao Zhen Wei, Wenyi Wulf, Gerburg M. Lu, Kun Ping |
author_sort | Ke, Shizhong |
collection | PubMed |
description | Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C(CDH1)), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/C(CDH1) regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/C(CDH1) E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/C(CDH1) itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/C(CDH1) inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C(CDH1) resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/C(CDH1) is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy. |
format | Online Article Text |
id | pubmed-9882653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-98826532023-01-28 Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability Ke, Shizhong Dang, Fabin Wang, Lin Chen, Jia-Yun Naik, Mandar T. Thavamani, Abhishek Liu, Yansheng Li, Wenxue Kim, Nami Naik, Nandita M. Sui, Huaxiu Tang, Wei Qiu, Chenxi Koikawa, Kazuhiro Batalini, Felipe Wang, Xiaodong Clohessy, John G. Heng, Yujing Jan Lahav, Galit Gray, Nathanael S. Zho, Xiao Zhen Wei, Wenyi Wulf, Gerburg M. Lu, Kun Ping Res Sq Article Cyclin-dependent kinases (CDKs) mediated phosphorylation inactivates the anaphase-promoting complex (APC/C(CDH1)), an E3 ubiquitin ligase that contains the co-activator CDH1, to promote G1/S transition. PIN1 is a phosphorylation-directed proline isomerase and a master cancer signaling regulator. However, little are known about APC/C(CDH1) regulation after phosphorylation and about PIN1 ubiquitin ligases. Here we uncover a domain-oriented reciprocal inhibition that controls the timely G1/S transition: The non-phosphorylated APC/C(CDH1) E3 ligase targets PIN1 for degradation in G1 phase, restraining G1/S transition; APC/C(CDH1) itself, after phosphorylation by CDKs, is inactivated by PIN1-catalyzed isomerization, promoting G1/S transition. In cancer, PIN1 overexpression and APC/C(CDH1) inactivation reinforce each other to promote uncontrolled proliferation and tumorigenesis. Importantly, combined PIN1- and CDK4/6-inhibition reactivates APC/C(CDH1) resulting in PIN1 degradation and an insurmountable G1 arrest that translates into synergistic anti-tumor activity against triple-negative breast cancer in vivo. Reciprocal inhibition of PIN1 and APC/C(CDH1) is a novel mechanism to control timely G1/S transition that can be harnessed for synergistic anti-cancer therapy. American Journal Experts 2023-01-19 /pmc/articles/PMC9882653/ /pubmed/36711754 http://dx.doi.org/10.21203/rs.3.rs-2447544/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Ke, Shizhong Dang, Fabin Wang, Lin Chen, Jia-Yun Naik, Mandar T. Thavamani, Abhishek Liu, Yansheng Li, Wenxue Kim, Nami Naik, Nandita M. Sui, Huaxiu Tang, Wei Qiu, Chenxi Koikawa, Kazuhiro Batalini, Felipe Wang, Xiaodong Clohessy, John G. Heng, Yujing Jan Lahav, Galit Gray, Nathanael S. Zho, Xiao Zhen Wei, Wenyi Wulf, Gerburg M. Lu, Kun Ping Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title | Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title_full | Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title_fullStr | Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title_full_unstemmed | Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title_short | Reciprocal inhibition of PIN1 and APC/C(CDH1) controls timely G1/S transition and creates therapeutic vulnerability |
title_sort | reciprocal inhibition of pin1 and apc/c(cdh1) controls timely g1/s transition and creates therapeutic vulnerability |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882653/ https://www.ncbi.nlm.nih.gov/pubmed/36711754 http://dx.doi.org/10.21203/rs.3.rs-2447544/v1 |
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