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

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)

PDF 2024.02.26.582171v1.full.pdf - Submitted Version Available under License Creative Commons Attribution Non-commercial. Download (2MB)

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:	Klingbeil, Olaf Skopelitis, Damianos Tonelli, Claudia Aggarwal, Disha Russo, Suzanne Ha, Taehoon Spector, David L. Tuveson, David A. Cifani, Paolo Vakoc, Christopher R. Alpsoy, Aktan Demerdash, Osama E. Minicozzi, Francesca
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:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41471

Actions (login required)

Administrator's edit/view item