Journal
SCIENCE
Volume 331, Issue 6016, Pages 468-472Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1198946
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Funding
- Nancy Newton Loeb Pediatric Cancer Research
- Helen L. Kay Pediatric Cancer Research Award
- National Institute of Child Health and Human Development, NIH [T32-HD07513]
- National Heart, Lung, and Blood Institute, NIH [T32-HL007622-21A2]
- Research Foundation-Flanders (FWO)
- Belgian Foundation against Cancer
- Shirley K. Schlafer Foundation
- Elizabeth Caroline Crosby Fund
- University of Michigan Comprehensive Cancer Center [G007839]
- Leukemia and Lymphoma Research UK
- National Cancer Institute NIH [R01CA124540]
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Proper regulation of nuclear factor kappa B (NF-kappa B) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappa B signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappa B-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappa B signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappa B pathway in B lymphoproliferative disease.
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