PXD044829-1

PXD044829 is an original dataset announced via ProteomeXchange.

Title	MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer
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.
HostingRepository	PRIDE
AnnounceDate	2024-07-25
AnnouncementXML	Submission_2024-07-25_09:45:36.196.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Paolo Cifani
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-24 08:24:56	ID requested
⏵ 1	2024-07-25 09:45:36	announced

Dataset with its publication pending

submitter keyword: Phosphorylation Hippo pathway MARK2/3

Paolo Cifani
contact affiliation	Mass Spectrometry Shared Resource, Cold Spring Harbor Laboratory
contact email	cshl.mass.spec@gmail.com
lab head
Paolo Cifani
contact affiliation	Cold Spring Harbor Laboratory
contact email	cshl.mass.spec@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD044829
     1. Label: PRIDE project
     2. Name: MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer