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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242517 | GEO | 2024/07/19

REPOSITORIES: GEO

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

Project description:Human cancer is often caused by dysfunctional developmental pathways, but such mechanisms do not always present clear opportunities for therapeutic intervention. This is exemplified by the Hippo tumor suppressor pathway, which is comprised of a kinase module that restrains the function of YAP/TAZ transcriptional coactivators; a pathway that becomes dysregulated in a wide array of human cancers. Hence, YAP/TAZ hyperactivation is a tumorigenic mechanism and a validated therapeutic target in oncology. In this study, we used a paralog co-targeting genetic screening strategy to identify the kinases MARK2/3 as co-dependencies of YAP/TAZ in diverse cancer contexts. We use biochemical and epistasis experiments to show that MARK2/3 phosphorylate and inhibit the activity of Hippo pathway components NF2, MST1/2, and MAP4Ks, which leads to indirect upstream control of LATS1/2 activity. In addition, MARK2/3 directly phosphorylate YAP/TAZ to shield these coactivators from LATS1/2-mediated inhibition. The net consequence of this multi-level regulation is that YAP/TAZ-dependent human cancers have an absolute requirement for MARK2/3 catalytic activity to sustain tumor cell proliferation and viability. To simulate therapeutic targeting of MARK2/3 in vivo, we adapted the EPIYA-repeat region of the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show exerts potent anti-tumor activity via on-target mechanisms. Together, these findings reveal MARK2/3 as an obligate catalytic requirement for YAP/TAZ function in human cancer; kinase targets that may allow for novel pharmacology that restores Hippo-mediated tumor suppression.

2024-07-25 | PXD044829 | Pride

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer (part2)

2024-07-25 | PXD054192 | Pride

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [RNA-seq]

Project description:The effect of gene perturbation on the transcriptome was evaluated in human Cas9 expressing cancer cell lines

2024-07-20 | GSE242516 | GEO

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [CUT&RUN]

Project description:The effect of gene perturbation on the histone mark H3K27ac was evaluated in human Cas9 expressing MDA-MB231 cancers

2024-07-20 | GSE241897 | GEO

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

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

| PRJNA1013786 | ENA

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [RNA-seq]

Project description:MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [RNA-seq]

| PRJNA1013790 | ENA

MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [CUT&RUN]

Project description:MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer [CUT&RUN]

| PRJNA1010710 | ENA

Tead2 expression levels control the subcellular distribution of Yap and Taz, zyxin expression and epithelial-mesenchymal transition

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-03-12 | E-GEOD-55711 | biostudies-arrayexpress

Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-23 | E-GEOD-50625 | biostudies-arrayexpress

YAP/TAZ-dependent expression of lncRNAs

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-15 | GSE207724 | GEO

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