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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
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
_version_ 1784879338339958784
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
work_keys_str_mv AT keshizhong reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT dangfabin reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT wanglin reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT chenjiayun reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT naikmandart reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT thavamaniabhishek reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT liuyansheng reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT liwenxue reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT kimnami reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT naiknanditam reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT suihuaxiu reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT tangwei reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT qiuchenxi reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT koikawakazuhiro reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT batalinifelipe reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT wangxiaodong reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT clohessyjohng reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT hengyujingjan reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT lahavgalit reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT graynathanaels reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT zhoxiaozhen reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT weiwenyi reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT wulfgerburgm reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability
AT lukunping reciprocalinhibitionofpin1andapcccdh1controlstimelyg1stransitionandcreatestherapeuticvulnerability