2. Academic Validation
  3. Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis

Stabilization of Motin family proteins in NF2-deficient cells prevents full activation of YAP/TAZ and rapid tumorigenesis

  • Cell Rep. 2021 Aug 24;36(8):109596. doi: 10.1016/j.celrep.2021.109596.
Yu Wang 1,  Yuwen Zhu 1,  Yuan Gu 1,  Mingyue Ma 1,  Yebin Wang 1,  Sixian Qi 1,  Yan Zeng 1,  Rui Zhu 1,  Xueying Wang 1,  Pengcheng Yu 1,  Jianhui Xu 2,  Yilai Shu 2,  Fa-Xing Yu 3
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 2 ENT Institute and Otorhinolaryngology, Department of Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, China.
  • 3 Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: fxyu@fudan.edu.cn.
PMID: 34433060 DOI: 10.1016/j.celrep.2021.109596
Abstract

Germline alterations of the NF2 gene cause neurofibromatosis type 2, a syndrome manifested with benign tumors, and Nf2 deletion in mice also results in slow tumorigenesis. As a regulator of the Hippo signaling pathway, NF2 induces LATS1/2 kinases and consequently represses YAP/TAZ. YAP/TAZ oncoproteins are also inhibited by motin family proteins (Motins). Here, we show that the Hippo signaling is fine-tuned by Motins in a NF2-dependent manner, in which NF2 recruits E3 Ligase RNF146 to facilitate ubiquitination and subsequent degradation of Motins. In the absence of NF2, Motins robustly accumulate to restrict full activation of YAP/TAZ and prevent rapid tumorigenesis. Hence, NF2 deficiency not only activates YAP/TAZ by inhibiting LATS1/2 but also stabilizes Motins to keep YAP/TAZ activity in check. The upregulation of Motins upon NF2 deletion serves as a strategy for avoiding uncontrolled perturbation of the Hippo signaling and may contribute to the benign nature of most NF2-mutated tumors.

Keywords

Hippo signaling; NF2; RNF146; TNKS1/2; YAP; neurofibromatosis type 2.

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