A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas

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2019-02-15
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American English
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Oxford University Press
Abstract

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

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Gehlhausen, J. R., Hawley, E., Wahle, B. M., He, Y., Edwards, D., Rhodes, S. D., Lajiness, J. D., Staser, K., Chen, S., Yang, X., Yuan, J., Li, X., Jiang, L., Smith, A., Bessler, W., Sandusky, G., Stemmer-Rachamimov, A., Stuhlmiller, T. J., Angus, S. P., Johnson, G. L., … Park, S. J. (2019). A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas. Human molecular genetics, 28(4), 572–583. https://doi.org/10.1093/hmg/ddy361
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Human Molecular Genetics
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PMC
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