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MEK1–RSK2 contributes to hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination

Oncogene volume 33, pages 65–73 (2014)Cite this article

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Abstract

The transcription factor GLI2 has an important role in the transduction of Hedgehog signaling and thereby regulates tumorigenesis in a wide variety of human tumors. However, the mechanisms controlling GLI2 protein expression and stabilization are incompletely understood. In this study, we show that the mitogen-activated protein kinase MEK1 modulates GLI2 both at the mRNA and protein level. Constitutively activated MEK1 prolonged the half-life of GLI2 and increased its nuclear translocation, accompanied by attenuated ubiquitination of GLI2 protein. RSK2, a protein kinase lying downstream of MEK–ERK cascade, mimicked the effect of MEK on GLI2 stabilization. MEK1 and RSK2 failed to augment the half-life of GLI2 lacking GSK-3β phosphorylation sites, indicating that MEK–RSK stabilizes GLI2 by controlling targeting GSK-3β-mediated phosphorylation and ubiquitination of GLI2. The significance of MEK–RSK stabilization was demonstrated in experiments showing that activation of MEK–RSK paralleled higher protein level of GLI2 in several multiple myelomas (MM) cells relative to normal B cells. Moreover, combined treatment with RSK and GLI inhibitors led to an enhanced apoptosis of MM cells. Thus, our results indicate that MEK–RSK cascade positively regulates GLI2 stabilization and represses its degradation via inhibiting GSK-3β-dependent phosphorylation and ubiquitination of GLI2.

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Acknowledgements

This work was supported by National Institutes of Health R01 (AR053100) (M C Naski), the National Natural Sciences Foundation of China (31101057), and the Sciences Foundation of Zhejiang Normal University (ZC304009172). We thank Dr Natalia Riobo from Thomas Jefferson University; Dr John Blenis from Department of Cell Biology of Harvard Medical School; Dr Richard L Huganir from the Department of Neuroscience of Howard Hughes Medical Institute; Dr Fritz Aberger, University of Salzburg; and Dr Baolin Wang, Associate Professor of Cell and Developmental Biology Weill Cornell Medical College, for their generous contributions of the plasmids used in this study.

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Authors and Affiliations

  1. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Z Liu, M I Reinhold & M C Naski

  2. Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Liu

  3. Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China

    T Li

  4. Department of Physician Assistant Studies, Grand Valley State University, Grand Rapids, MI, USA

    M I Reinhold

  5. Department of Pathology, St Mary’s Health Care, Grand Rapids, MI, USA

    M C Naski

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  1. Z Liu
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Correspondence to Z Liu or M C Naski.

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Liu, Z., Li, T., Reinhold, M. et al. MEK1–RSK2 contributes to hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination. Oncogene 33, 65–73 (2014). https://doi.org/10.1038/onc.2012.544

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