title: Protease activity of the API2-MALT1 fusion oncoprotein in MALT lymphoma development and treatment.
abstract: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a prototypical cancer that occurs in the setting of chronic inflammation and an important model for understanding how deregulated NF-κB transcriptional activity contributes to malignancy. Most gastric MALT lymphomas require ongoing antigenic stimulation for continued tumor growth, and Stage I disease is usually cured by eradicating the causative microorganism, Helicobacter pylori, with antibiotics. However, in a subset of MALT lymphomas, chromosomal translocations are acquired that render the lymphoma antigen-independent. The recurrent translocation t(11;18)(q21;q21) is associated with failure to respond to antibiotic therapy and increased rate of dissemination. This translocation creates the API2-MALT1 fusion oncoprotein, which comprises the amino terminus of inhibitor of apoptosis 2 (API2 or cIAP2) fused to the carboxy terminus of MALT1. A common characteristic of chromosomal translocations in MALT lymphoma, including t(11;18), is that genes involved in the regulation of the NF-κB transcription factor are targeted by the translocations, and these genetic perturbations thereby result in deregulated, constitutive NF-κB stimulation. In the last decade, great insights into the roles of API2 and MALT1 in NF-κB signaling have been made. For example, recent pivotal studies have uncovered the long sought-after proteolytic activity of MALT1 and have demonstrated its critical involvement in the survival of certain lymphomas. Here, we review the current understanding of the role of MALT1 in normal lymphocyte function and lymphomagenesis. We then highlight our recent work that has revealed an intriguing link between the proteolytic activity of the API2-MALT1 fusion and its ability to influence lymphomagenesis by cleaving a key NF-κB regulatory protein, NF-κB-inducing kinase.
authors.affiliation: Department of Pediatrics & 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: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.forename: Linda M
authors.initials: LM
authors.lastname: McAllister-Lucas
mesh_terms: D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: C415943:API2-MALT1 fusion protein, human; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D010447:Peptide Hydrolases