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PMID: 21273489 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Science (New York, N.Y.) ·Vol. 331 ·No. 6016 ·2011-01-28 ·Pages 468-72

Rosebeck S, Madden L, Jin X, Gu S, Apel IJ, Appert A, Hamoudi RA, Noels H, Sagaert X, Van Loo P, Baens M, Du MQ, Lucas PC, McAllister-Lucas LM

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.

MeSH Terms
Apoptosis B-Lymphocytes/metabolism Cell Adhesion Cell Line Cell Line, Tumor Gene Expression Regulation, Neoplastic Humans I-kappa B Kinase/metabolism Lymphoma, B-Cell, Marginal Zone/genetics,metabolism NF-kappa B/metabolism NF-kappa B p52 Subunit/metabolism Oncogene Proteins, Fusion/chemistry,genetics,metabolism Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Protein Structure, Tertiary Proto-Oncogene Proteins/genetics,metabolism Signal Transduction Substrate Specificity
Chemicals
API2-MALT1 fusion protein, human NF-kappa B NF-kappa B p52 Subunit Oncogene Proteins, Fusion PIM2 protein, human Proto-Oncogene Proteins Protein Serine-Threonine Kinases I-kappa B Kinase NF-kappa B kinase
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Rosebeck Shaun
Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Madden Lisa
Jin Xiaohong
Gu Shufang
Apel Ingrid J
Appert Alex
Hamoudi Rifat A
Noels Heidi
Sagaert Xavier
Van Loo Peter
Baens Mathijs
Du Ming-Qing
Lucas Peter C
McAllister-Lucas Linda M
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1198946
Published
2011-01-28
Pages
468-72
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3124150
Subset
IM
Grants
NICHD NIH HHS · T32-HD07513 · United States
NHLBI NIH HHS · T32-HL007622-21A2 · United States
NCI NIH HHS · R01 CA124540 · United States
NHLBI NIH HHS · R01 HL082914 · United States
NCI NIH HHS · R01 CA124540-04 · United States
NCI NIH HHS · R01CA124540 · United States
Databases
GEO
GSE25527, GSE25550
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1126/science.1198946 PMC Full Text View journal details
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