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

Klingbeil, Olaf, Skopelitis, Damianos, Tonelli, Claudia, Yoshimoto, Toyoki, Alpsoy, Aktan, Panepinto, Maria C, Minicozzi, Francesca, Merrill, Joseph R, Cafiero, Amanda M, Aggarwal, Disha, Russo, Suzanne, Ha, Taehoon, Demerdash, Osama E, Wee, Tse-Luen, Spector, David L, Lyons, Scott K, Tuveson, David A, Cifani, Paolo, Vakoc, Christopher R (July 2024) MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer. Cancer Discovery. ISSN 2159-8274 (Public Dataset)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/39058094

DOI: 10.1158/2159-8290.CD-23-1529

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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders
CSHL Authors:	Klingbeil, Olaf Skopelitis, Damianos Tonelli, Claudia Merrill, Joseph Aggarwal, Disha Russo, Suzanne Ha, Taehoon Wee, Tse-Luen Spector, David L. Lyons, Scott Tuveson, David A. Cifani, Paolo Vakoc, Christopher R. Yoshimoto, Toyoki Alpsoy, Aktan Minicozzi, Francesca Cafiero, Amanda Demerdash, Osama E.
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Kinney lab CSHL labs > Lyons lab CSHL labs > Spector lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab CSHL Cancer Center Program CSHL labs > Wee Lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	26 July 2024
Date Deposited:	29 Jul 2024 13:08
Last Modified:	29 Jul 2024 13:08
Related URLs:	Publisher
Dataset ID:	GEO: GSE242517 PRIDE: PXD044829 GEO: GSE140484 https://doi.org/10.5281/zenodo.10042504
URI:	https://repository.cshl.edu/id/eprint/41624

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