激酶
癌症
心理学
癌症研究
业务
医学
细胞生物学
生物
内科学
作者
Olaf Klingbeil,Damianos S. Skopelitis,C. Tonelli,Aktan Alpsoy,Francesca Minicozzi,Disha Aggarwal,Suzanne Russo,Taehoon Ha,Osama E. Demerdash,David L. Spector,David A. Tuveson,Paolo Cifani,Christopher R. Vakoc
标识
DOI:10.1101/2024.02.26.582171
摘要
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 exerts anti-tumor activity 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.
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