title: Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Rosebeck
authors.forename: Lisa
authors.initials: L
authors.lastname: Madden
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Jin
authors.forename: Shufang
authors.initials: S
authors.lastname: Gu
authors.forename: Ingrid J
authors.initials: IJ
authors.lastname: Apel
authors.forename: Alex
authors.initials: A
authors.lastname: Appert
authors.forename: Rifat A
authors.initials: RA
authors.lastname: Hamoudi
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.forename: Xavier
authors.initials: X
authors.lastname: Sagaert
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.forename: Mathijs
authors.initials: M
authors.lastname: Baens
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Du
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.forename: Linda M
authors.initials: LM
authors.lastname: McAllister-Lucas
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D015514:Oncogene Proteins, Fusion; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097782:NF-kappaB-Inducing Kinase; C415943:API2-MALT1 fusion protein, human; C490587:PIM2 protein, human