MARK2/MARK3 Kinases Are Catalytic Codependencies of YAP/TAZ in Human Cancer

Klingbeil O., Skopelitis D., Tonelli C., Yoshimoto T., ALPSOY A., Panepinto M. C., ...Daha Fazla

CANCER DISCOVERY, cilt.14, sa.12, ss.2471-2488, 2024 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 14 Sayı: 12
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1158/2159-8290.cd-23-1529
  • Dergi Adı: CANCER DISCOVERY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, BIOSIS, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.2471-2488
  • Orta Doğu Teknik Üniversitesi Adresli: Hayır

Özet

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