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

Jeffrey R. Gehlhausen, Eric Hawley, Benjamin Mark Wahle, Yongzheng He, Donna Edwards, Steven D. Rhodes, Jacquelyn D. Lajiness, Karl Staser, Shi Chen, Xianlin Yang, Jin Yuan, Xiaohong Li, Li Jiang, Abbi Smith, Waylan Bessler, George Sandusky, Anat Stemmer-Rachamimov, Timothy J. Stuhlmiller, Steven P. Angus, Gary L. Johnson & 4 others Grzegorz Nalepa, Charles Yates, D. Clapp, Su Jung Park

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)572-583
Number of pages12
JournalHuman Molecular Genetics
Volume28
Issue number4
DOIs
StatePublished - Feb 15 2019

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Neurilemmoma
Proteasome Endopeptidase Complex
Neurofibromin 2
Phosphotransferases
Schwann Cells
Proto-Oncogene Proteins c-met
Cell Proliferation
Neurofibromatosis 2
Neoplasms
Mutation
Hepatocyte Growth Factor
Caspases
Germ Cells
B-Lymphocytes
Transplants
Light
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Gehlhausen, J. R., Hawley, E., Wahle, B. M., He, Y., Edwards, D., Rhodes, S. D., ... 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

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas. / Gehlhausen, Jeffrey R.; Hawley, Eric; Wahle, Benjamin Mark; He, Yongzheng; Edwards, Donna; Rhodes, Steven D.; Lajiness, Jacquelyn D.; Staser, Karl; Chen, Shi; Yang, Xianlin; Yuan, Jin; Li, Xiaohong; Jiang, Li; Smith, Abbi; Bessler, Waylan; Sandusky, George; Stemmer-Rachamimov, Anat; Stuhlmiller, Timothy J.; Angus, Steven P.; Johnson, Gary L.; Nalepa, Grzegorz; Yates, Charles; Clapp, D.; Park, Su Jung.

In: Human Molecular Genetics, Vol. 28, No. 4, 15.02.2019, p. 572-583.

Research output: Contribution to journalArticle

Gehlhausen, JR, Hawley, E, Wahle, BM, He, Y, Edwards, D, Rhodes, SD, Lajiness, JD, Staser, K, Chen, S, Yang, X, Yuan, J, Li, X, Jiang, L, Smith, A, Bessler, W, Sandusky, G, Stemmer-Rachamimov, A, Stuhlmiller, TJ, Angus, SP, Johnson, GL, Nalepa, G, Yates, C, Clapp, D & Park, SJ 2019, 'A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas', Human Molecular Genetics, vol. 28, no. 4, pp. 572-583. https://doi.org/10.1093/hmg/ddy361
Gehlhausen JR, Hawley E, Wahle BM, He Y, Edwards D, Rhodes SD et al. A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas. Human Molecular Genetics. 2019 Feb 15;28(4):572-583. https://doi.org/10.1093/hmg/ddy361
Gehlhausen, Jeffrey R. ; Hawley, Eric ; Wahle, Benjamin Mark ; He, Yongzheng ; Edwards, Donna ; Rhodes, Steven D. ; Lajiness, Jacquelyn D. ; Staser, Karl ; Chen, Shi ; Yang, Xianlin ; Yuan, Jin ; Li, Xiaohong ; Jiang, Li ; Smith, Abbi ; Bessler, Waylan ; Sandusky, George ; Stemmer-Rachamimov, Anat ; Stuhlmiller, Timothy J. ; Angus, Steven P. ; Johnson, Gary L. ; Nalepa, Grzegorz ; Yates, Charles ; Clapp, D. ; Park, Su Jung. / A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas. In: Human Molecular Genetics. 2019 ; Vol. 28, No. 4. pp. 572-583.
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AU - Rhodes, Steven D.

AU - Lajiness, Jacquelyn D.

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AU - Yuan, Jin

AU - Li, Xiaohong

AU - Jiang, Li

AU - Smith, Abbi

AU - Bessler, Waylan

AU - Sandusky, George

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AU - Angus, Steven P.

AU - Johnson, Gary L.

AU - Nalepa, Grzegorz

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