Supplementary Table S6 from MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer

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posted on 2024-12-02, 08:41 authored by 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

FDR for synergy score paralog combinations. Table of FDR corresponding to synergy scores calculated using GEMINI.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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Deutsche Forschungsgemeinschaft (DFG)

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ARTICLE ABSTRACT

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the 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 Helicobacter 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 codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway–mediated tumor suppression.Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas.See related commentary by Gauthier-Coles and Sheltzer, p. 2312

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Keywords

Cell Signaling Drug Targets Protein kinase & phosphatase drug targets Oncogenes & Tumor Suppressors

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