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Science 331 (6016): 468-472

Copyright © 2011 by the American Association for the Advancement of Science

Cleavage of NIK by the API2-MALT1 Fusion Oncoprotein Leads to Noncanonical NF-{kappa}B Activation

Shaun Rosebeck,1,{ddagger} Lisa Madden,1,*,{ddagger} Xiaohong Jin,2 Shufang Gu,1 Ingrid J. Apel,2 Alex Appert,3 Rifat A. Hamoudi,3 Heidi Noels,4,5,{dagger} Xavier Sagaert,6 Peter Van Loo,4,5 Mathijs Baens,4,5 Ming-Qing Du,3 Peter C. Lucas,2,§ Linda M. McAllister-Lucas1,§

Abstract: 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.

1 Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
2 Department of Pathology, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
3 Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Laboratory Block, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK.
4 Human Genome Laboratory, Molecular Genetics, Center for Human Genetics, Catholic University Leuven, B-3000 Leuven, Belgium.
5 Human Genome Laboratory, Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), B-3000 Leuven, Belgium.
6 Section of Morphology and Molecular Pathology, Department of Pathology, Catholic University Leuven, B-3000 Leuven, Belgium.

* Present address: Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

{dagger} Present address: Institute for Molecular Cardiovascular Research, RWTH Aachen University, 52074 Aachen, Germany.

{ddagger} These authors contributed equally to the work.

§ To whom correspondence should be addressed. E-mail: plucas{at}umich.edu (P.C.L.); lindaluc{at}umich.edu (L.M.M-L.)


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