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
  • 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: [email protected].
  • 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: [email protected].
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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