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Hum Mol Genet. 2019 Feb 15;28(4):572-583. doi: 10.1093/hmg/ddy361.

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

Author information

1
Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
2
Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN, USA.
3
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Department of Medicine, Division of Dermatology, Washington University in Saint Louis, St. Louis, MO, USA.
5
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.
6
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
7
Department of Pharmacology, University of North Carolina, Chapel Hill, NC.
8
Department of Otolaryngology, Indiana University School of Medicine, Indianapolis, IN, USA.
9
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.

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.

PMID:
30335132
PMCID:
PMC6489415
[Available on 2020-02-15]
DOI:
10.1093/hmg/ddy361

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