Details

Autor(en) / Beteiligte

• Wang, Yu
• Zhu, Yuwen
• Gu, Yuan
• Ma, Mingyue
• Wang, Yebin
• Qi, Sixian
• Zeng, Yan
• Zhu, Rui
• Wang, Xueying
• Yu, Pengcheng
• Xu, Jianhui
• Shu, Yilai
• Yu, Fa-Xing

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2021-08, Vol.36 (8), p.109596-109596, Article 109596

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Motins are destabilized upon serum or LPA treatment in a NF2-dependent manner•NF2 recruits RNF146 to Motins, promoting ubiquitination and degradation of Motins•Inactivation of Motins in NF2-deficient cells enhances oncogenic activity of YAP•High AMOT expression in NF2-null mesotheliomas is associated with good prognosis NF2 is a regulator of the Hippo tumor suppressor pathway. Wang et al. show that motin family proteins (Motins) are stabilized in the absence of NF2, which prevents full activation of YAP/TAZ oncoproteins and rapid tumorigenesis. This mechanism may contribute to the benign nature of tumors driven by NF2 deficiency.