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MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression

The Hippo signaling axis is a tumor suppressor pathway that is activated by various extra‐pathway factors to regulate cell differentiation and organ development. Recent studies have reported that autophosphorylation of the core kinase cassette stimulates activation of the Hippo signaling cascade. He...

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Autores principales: Sun, Yan, Jin, Xin, Meng, Junpeng, Guo, Feng, Chen, Taoyu, Zhao, Xiaoyan, Wu, Heshui, Ren, Dianyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690468/
https://www.ncbi.nlm.nih.gov/pubmed/37905571
http://dx.doi.org/10.15252/embj.2023114558
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author Sun, Yan
Jin, Xin
Meng, Junpeng
Guo, Feng
Chen, Taoyu
Zhao, Xiaoyan
Wu, Heshui
Ren, Dianyun
author_facet Sun, Yan
Jin, Xin
Meng, Junpeng
Guo, Feng
Chen, Taoyu
Zhao, Xiaoyan
Wu, Heshui
Ren, Dianyun
author_sort Sun, Yan
collection PubMed
description The Hippo signaling axis is a tumor suppressor pathway that is activated by various extra‐pathway factors to regulate cell differentiation and organ development. Recent studies have reported that autophosphorylation of the core kinase cassette stimulates activation of the Hippo signaling cascade. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) contributes to inactivation of the Hippo signaling pathway in pancreatic cancer. We show that the Hippo pathway initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di‐methylated by PRMT5 at arginine‐461 (R461) and arginine‐467 (R467) in its SARAH domain. Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also show that the specific PRMT5 inhibitor GSK3326595 re‐activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic cancer.
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spelling pubmed-106904682023-12-02 MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression Sun, Yan Jin, Xin Meng, Junpeng Guo, Feng Chen, Taoyu Zhao, Xiaoyan Wu, Heshui Ren, Dianyun EMBO J Articles The Hippo signaling axis is a tumor suppressor pathway that is activated by various extra‐pathway factors to regulate cell differentiation and organ development. Recent studies have reported that autophosphorylation of the core kinase cassette stimulates activation of the Hippo signaling cascade. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) contributes to inactivation of the Hippo signaling pathway in pancreatic cancer. We show that the Hippo pathway initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di‐methylated by PRMT5 at arginine‐461 (R461) and arginine‐467 (R467) in its SARAH domain. Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also show that the specific PRMT5 inhibitor GSK3326595 re‐activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic cancer. John Wiley and Sons Inc. 2023-10-31 /pmc/articles/PMC10690468/ /pubmed/37905571 http://dx.doi.org/10.15252/embj.2023114558 Text en © 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Sun, Yan
Jin, Xin
Meng, Junpeng
Guo, Feng
Chen, Taoyu
Zhao, Xiaoyan
Wu, Heshui
Ren, Dianyun
MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title_full MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title_fullStr MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title_full_unstemmed MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title_short MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression
title_sort mst2 methylation by prmt5 inhibits hippo signaling and promotes pancreatic cancer progression
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690468/
https://www.ncbi.nlm.nih.gov/pubmed/37905571
http://dx.doi.org/10.15252/embj.2023114558
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