MAML1/2 promote YAP/TAZ nuclear localization and tumorigenesis.
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.
['Kim|Jiyoung|J|', 'Kwon|Hyeryun|H|', 'Shin|You Keun|YK|', 'Song|Gahyeon|G|', 'Lee|Taebok|T|0000-0002-8390-6670', 'Kim|Youngeun|Y|', 'Jeong|Wonyoung|W|', 'Lee|Ukjin|U|', 'Zhang|Xianglan|X|', 'Nam|Gilyeong|G|', 'Jeung|Hei-Cheul|HC|', 'Kim|Wantae|W|', 'Jho|Eek-Hoon|EH|0000-0003-2414-6234']
D048868:Adaptor Proteins, Signal Transducing D063646:Carcinogenesis D002467:Cell Nucleus D004268:DNA-Binding Proteins D006801:Humans D035683:MicroRNAs D009369:Neoplasms D021381:Protein Transport D015398:Signal Transduction D015534:Trans-Activators D014157:Transcription Factors D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins D000091102:YAP-Signaling Proteins
MAML1/2 YAP/TAZ nuclear localization Hippo signaling TEAD