MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.

IF 29.7 1区 医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2024-07-26 DOI:10.1158/2159-8290.CD-23-1529
Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc
{"title":"MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.","authors":"Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc","doi":"10.1158/2159-8290.CD-23-1529","DOIUrl":null,"url":null,"abstract":"<p><p>The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-23-1529","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
在人类癌症中,MARK2/MARK3 激酶是 YAP/TAZ 的催化共依赖因子。
在人类癌症中,Hippo 信号通路普遍失调,导致肿瘤对 YAP/TAZ 转录辅激活因子产生强大的依赖性。在这里,我们利用旁系共同靶向 CRISPR 筛选确定了激酶 MARK2/3 是 YAP/TAZ 在各种癌症和肉瘤中发挥功能的绝对催化条件。这一观察结果的基础是 MARK2/3 对 NF2 和 YAP/TAZ 的直接磷酸化,它能有效逆转 Hippo 模块激酶 LATS1/2 的肿瘤抑制活性。为了模拟MARK2/3的靶向作用,我们将幽门螺杆菌中的CagA蛋白作为MARK2/3的催化抑制剂,结果表明它能使体内已形成的肿瘤消退。这些发现共同揭示了MARK2/3在人类癌症中与YAP/TAZ的强大协同依赖关系;这些靶点可能是恢复Hippo通路介导的肿瘤抑制的药理学靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
期刊介绍: Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.
期刊最新文献
Clinical Validation of a Cell-Free DNA Fragmentome Assay for Augmentation of Lung Cancer Early Detection. The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma. Single-Cell View of Tumor Microenvironment Gradients in Pleural Mesothelioma. A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer. Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1