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Phosphorylation of Mps1 by BRAFV600E prevents Mps1 degradation and contributes to chromosome instability in melanoma

Oncogene volume 32, pages 713–723 (2013)Cite this article

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Abstract

Activating BRAF mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. BRAFV600E induces centrosome amplification and spindle abnormalities that result in aneuploidy. We find modification of Mps1 is critical for contributing to centrosome amplification and chromosome instability induced by BRAFV600E. Phosphorylation of Mps1 at residue S281 induced by BRAFV600E stabilizes Mps1 protein by preventing its ubiquitination by APC/C and subsequent degradation, allowing the non-degraded protein to accumulate at centrosomes. Cells in which endogenous Mps1 was replaced with a phospho-mimetic Mps1 mutant are viable but amplify centrosomes and missegregate chromosomes frequently. Importantly, analysis of tumor micro arrays revealed that phospho-MAPK and S281-phosphorylated Mps1 were highly correlated in human melanoma tissues, implying that MAPK contributes to defects in the degradation of Mps1 in situ. We propose that continuously activated BRAFV600E signaling may be a possible mechanism for the deregulation of Mps1 stability and kinase activity in human tumors, and that persistent phosphorylation of Mps1 through BRAFV600E signaling is a key event in disrupting the control of centrosome duplication and chromosome stability that may contribute to tumorigenesis. Our findings raise the possibility that targeting the oncogenic BRAF and S281-phosphorylated Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment.

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Acknowledgements

We thank Kenji Fukasawa (H Lee Moffitt Cancer Center) for critical reading of this article. This work was supported by the Program for New Century Excellent Talents University of China (Grant NCET-10-0872), National Nature Science Foundation of China (Grant 30872932 & 30971518), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (Grant 2009-8), Shanxi Province Foundation for Returness (2008-49), Trainee Development Award from Bankhead Coley Program (Grant 30-15066-02-07) to YC and National Nature Science Foundation of China (Grant 81071625), Program for the Top Young Academic Leaders of Higher Learning Institutions of Shanxi to XC.

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  1. J Liu, X Cheng and Y Zhang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, People's Republic of China

    J Liu & H Zhao

  2. Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, People's Republic of China

    J Liu, X Cheng, Y Zhang, S Li, H Cui, L Zhang, Z Zhao, C He, C Zhang & Y Cui

  3. Department of Cell Biology & Genetics, Shanxi Medical University, Taiyuan, People's Republic of China

    X Cheng, Y Zhang, S Li, H Cui, L Zhang, R Shi, Z Zhao, C He & Y Cui

  4. School of Life Science, East China Normal University, Shanghai, People's Republic of China

    C Wang

  5. Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA

    H A Fisk

  6. Department of Molecular Oncology, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    T M Guadagno

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  1. J Liu
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Correspondence to Y Cui.

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Liu, J., Cheng, X., Zhang, Y. et al. Phosphorylation of Mps1 by BRAFV600E prevents Mps1 degradation and contributes to chromosome instability in melanoma. Oncogene 32, 713–723 (2013). https://doi.org/10.1038/onc.2012.94

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