MAML1/2 promote YAP/TAZ nuclear localization and tumorigenesis

Jiyoung Kim, Hyeryun Kwon, You Keun Shin, Gahyeon Song, Taebok Lee, Youngeun Kim, Wonyoung Jeong, Ukjin Lee, Xianglan Zhang, Gilyeong Nam, Hei Cheul Jeung, Wantae Kim, Eek Hoon Jho

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The Hippo pathway plays a pivotal role in tissue homeostasis and tumor suppression. YAP and TAZ are downstream effectors of the Hippo pathway, and their activities are tightly suppressed by phosphorylation-dependent cytoplasmic retention. However, the molecular mechanisms governing YAP/TAZ nuclear localization have not been fully elucidated. Here, we report that Mastermind-like 1 and 2 (MAML1/2) are indispensable for YAP/TAZ nuclear localization and transcriptional activities. Ectopic expression or depletion of MAML1/2 induces nuclear translocation or cytoplasmic retention of YAP/TAZ, respectively. Additionally, mutation of the MAML nuclear localization signal, as well as its YAP/TAZ interacting region, both abolish nuclear localization and transcriptional activity of YAP/TAZ. Importantly, we demonstrate that the level of MAML1 messenger RNA (mRNA) is regulated by microRNA-30c (miR-30c) in a cell-density-dependent manner. In vivo and clinical results suggest that MAML potentiates YAP/TAZ oncogenic function and positively correlates with YAP/TAZ activation in human cancer patients, suggesting pathological relevance in the context of cancer development. Overall, our study not only provides mechanistic insight into the regulation of YAP/TAZ subcellular localization, but it also strongly suggests that the miR30c-MAML-YAP/TAZ axis is a potential therapeutic target for developing novel cancer treatments.

Original languageEnglish
Pages (from-to)13529-13540
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number24
DOIs
StatePublished - 16 Jun 2020

Keywords

  • Hippo signaling
  • MAML1/2
  • Nuclear localization
  • TEAD
  • YAP/TAZ

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