{"doi":"10.1158/2159-8290.cd-23-1529","title":"MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer","abstract":"The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the 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 Helicobacter 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 codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression. Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas. See related commentary by Gauthier-Coles and Sheltzer, p. 2312.","journal":"Cancer Discovery","year":2024,"id":422643,"datarank":0.49983067652628066,"base_score":3.332204510175204,"endowment":3.332204510175204,"self_citation_contribution":0.49983067652628066,"citation_network_contribution":0.0,"self_endowment_contribution":0.49983067652628066,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1071654,"name":"Damianos Skopelitis","orcid":"0000-0003-4724-5462","position":1,"is_corresponding":false},{"id":266272,"name":"Claudia Tonelli","orcid":"0000-0002-5626-3403","position":2,"is_corresponding":false},{"id":1217605,"name":"Toyoki Yoshimoto","orcid":null,"position":3,"is_corresponding":false},{"id":303985,"name":"Aktan Alpsoy","orcid":"0000-0002-8940-8277","position":4,"is_corresponding":false},{"id":1144569,"name":"Maria C. Panepinto","orcid":"0000-0001-7040-8181","position":5,"is_corresponding":false},{"id":1205454,"name":"Francesca Minicozzi","orcid":"0009-0007-7910-3342","position":6,"is_corresponding":false},{"id":611874,"name":"Joseph R. Merrill","orcid":"0000-0003-3680-1988","position":7,"is_corresponding":false},{"id":1217606,"name":"Amanda M. Cafiero","orcid":null,"position":8,"is_corresponding":false},{"id":236767,"name":"Disha Aggarwal","orcid":"0000-0002-5374-8165","position":9,"is_corresponding":false},{"id":173742,"name":"Suzanne Russo","orcid":null,"position":10,"is_corresponding":false},{"id":633987,"name":"Taehoon Ha","orcid":"0000-0002-4533-1140","position":11,"is_corresponding":false},{"id":558572,"name":"Osama E. Demerdash","orcid":"0000-0002-9896-2077","position":12,"is_corresponding":false},{"id":843887,"name":"Tse-Luen Wee","orcid":"0000-0002-4141-3157","position":13,"is_corresponding":false},{"id":236768,"name":"David L. Spector","orcid":"0000-0003-3614-4965","position":14,"is_corresponding":false},{"id":587997,"name":"Scott K. Lyons","orcid":"0000-0003-0139-6054","position":15,"is_corresponding":false},{"id":103976,"name":"David A. Tuveson","orcid":"0000-0002-8017-2712","position":16,"is_corresponding":false},{"id":574973,"name":"Paolo Cifani","orcid":"0000-0002-4403-1277","position":17,"is_corresponding":false},{"id":251322,"name":"Christopher R. Vakoc","orcid":"0000-0002-1158-7180","position":18,"is_corresponding":false},{"id":558571,"name":"Olaf Klingbeil","orcid":"0000-0001-7248-7506","position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:57:51.642883Z","pmid":"39058094","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}