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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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 |
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| Subjects: | diseases & disorders > cancer diseases & disorders |
| CSHL Authors: | |
| 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: | |
| Dataset ID: |
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| URI: | https://repository.cshl.edu/id/eprint/41624 |
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