Klingbeil, Olaf, Skopelitis, Damianos, Tonelli, Claudia, Alpsoy, Aktan, Minicozzi, Francesca, Aggarwal, Disha, Russo, Suzanne, Ha, Taehoon, Demerdash, Osama E, Spector, David L, Tuveson, David A, Cifani, Paolo, Vakoc, Christopher R (February 2024) MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer. bioRxiv. (Submitted)
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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 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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > CRISPR-Cas9 |
| CSHL Authors: | |
| Communities: | CSHL labs > Kinney lab CSHL labs > Spector lab CSHL labs > Tuveson lab CSHL labs > Vakoc lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 28 February 2024 |
| Date Deposited: | 20 Mar 2024 13:35 |
| Last Modified: | 20 Mar 2024 13:35 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41471 |
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