2. Academic Validation
  3. Smurf1 polyubiquitinates on K285/K282 of the kinases Mst1/2 to attenuate their tumor-suppressor functions

Smurf1 polyubiquitinates on K285/K282 of the kinases Mst1/2 to attenuate their tumor-suppressor functions

  • J Biol Chem. 2023 Oct 25:105395. doi: 10.1016/j.jbc.2023.105395.
Yana Xu 1,  Meiyu Qu 2,  Yangxun He 3,  Qiangqiang He 1,  Tingyu Shen 3,  Jiahao Luo 3,  Dan Tan 3,  Hangyang Bao 3,  Chengyun Xu 3,  Xing Ji 2,  Xinhua Hu 4,  Muhammad Qasim Barkat 3,  Ling-Hui Zeng 5,  Ximei Wu 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China.
  • 2 Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, 310015, China.
  • 3 Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 4 Department of Clinical Pharmacology, the Affiliated Second Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 5 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, Hangzhou City University School of Medicine, Hangzhou, 310015, China. Electronic address: zenglh@zucc.edu.cn.
  • 6 Department of Orthopaedics, the Affiliated Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China; Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, 310058, China. Electronic address: xiwu@zju.edu.cn.
PMID: 37890777 DOI: 10.1016/j.jbc.2023.105395
Abstract

Sterile 20-like kinases Mst1 and Mst2 (Mst1/2) and large tumor suppressor 1/2 (Lats1/2) are core kinases to mediate Hippo signaling in maintaining tissue homeostasis. We have previously demonstrated that Smad ubiquitin regulatory factor 1 (Smurf1), a HECT type E3 ligase, ubiquitinates and in turn destabilizes Lats1/2 to induce the transcriptional output of Hippo signaling. Here, we unexpectedly find that Smurf1 interacts with and polyubiquitinates Mst1/2 by virtue of K27- and K29-linked ubiquitin chains, resulting in the proteasomal degradation of Mst1/2 and attenuation of their tumor-suppressor functions. Among the potential ubiquitin acceptor sites on Mst1/2, K285/K282 are conserved and essential for Smurf1-induced polyubiquitination and degradation of Mst1/2 as well as transcriptional output of Hippo signaling. As a result, K285R/K282R mutation of Mst1/2 not only negates the transcriptional output of Hippo signaling but enhances the tumor-suppressor functions of Mst1/2. Together, we demonstrate that Smurf1-mediated polyubiquitination on K285/K282 of Mst1/2 destabilizes Mst1/2 to attenuate their tumor-suppressor functions. Thus, the present study identifies Smurf1-mediated ubiquitination of Mst1/2 as a hitherto uncharacterized mechanism fine-tuning the Hippo signaling pathway and may provide additional targets for therapeutic intervention of diseases associated with this important pathway.

Keywords

Hippo signaling; Mst1/2; Smurf1; Tumorigenesis; Ubiquitination.

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