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Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer

Oncogene volume 30, pages 781–789 (2011)Cite this article

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Abstract

The Neurofibromatosis-2 (NF2) tumor suppressor merlin negatively regulates cell proliferation in numerous cell types. We have previously shown that the NF2 protein (merlin/schwannomin) associates with mixed lineage kinase 3 (MLK3), a mitogen-activated protein kinase (MAPK) kinase kinase that is required for the proliferation of normal and neoplastic cells. In this study, we show that merlin inhibits MLK3 activity, as well as the activation of its downstream effectors, B-Raf, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). The ability of merlin to regulate MLK3 activity requires a direct association between MLK3 and residues in the C-terminal region of merlin. Merlin integrates Rho GTPase family signaling with MAPK activity by inhibiting the binding between MLK3 and its upstream activator, Cdc42. Furthermore, we demonstrate that MLK3 is required for merlin-mediated suppression of cell proliferation and invasion. Collectively, these results establish merlin as a potent inhibitor of MLK3, ERK and JNK activation in cancer, and provide a mechanistic link between deregulated MAPK and Rho GTPase signaling in NF2 growth control.

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Acknowledgements

We thank Dr J Kyriakis for the FLAG-Cdc42 constructs and Dr D Lim for HEI193 cells. This work was supported by National Institutes of Health Grant 1 R15 CA132006-01 and by an American Cancer Society (Ohio Division) grant (to D.N.C.).

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Authors and Affiliations

  1. Department of Biological Sciences, University of Toledo, Toledo, OH, USA

    Y Zhan, N Modi, A M Stewart, R I Hieronimus & D N Chadee

  2. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    J Liu

  3. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    D H Gutmann

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Correspondence to D N Chadee.

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Zhan, Y., Modi, N., Stewart, A. et al. Regulation of mixed lineage kinase 3 is required for Neurofibromatosis-2-mediated growth suppression in human cancer. Oncogene 30, 781–789 (2011). https://doi.org/10.1038/onc.2010.453

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