Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.

Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Science (Impact Factor: 31.48). 01/2011; 331(6016):468-72. DOI: 10.1126/science.1198946
Source: PubMed

ABSTRACT Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated
NF-κB 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-κB–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-κB 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-κB pathway in B lymphoproliferative disease.

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Available from: Rifat A Hamoudi, Jul 28, 2015
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