Bcl10 and MALT1, Independent Targets of Chromosomal Translocation in MALT Lymphoma, Cooperate in a Novel NF-κB Signaling Pathway

Division of Pediatric Genetics, University of Michigan, Ann Arbor, Michigan, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2001; 276(22):19012-9. DOI: 10.1074/jbc.M009984200
Source: PubMed

ABSTRACT At least two distinct recurrent chromosomal translocations have been implicated in the pathogenesis of MALT lymphoma. The first, t(1;14), results in the transfer of the entire Bcl10 gene to chromosome 14 wherein Bcl10 expression is inappropriately stimulated by the neighboring Ig enhancer. The second, t(11;18), results in the synthesis of a novel fusion protein, API2-MALT1. Until now, no common mechanism of action has been proposed to explain how the products of these seemingly unrelated translocations may contribute to the same malignant process. We show here that Bcl10 and MALT1 form a strong and specific complex within the cell, and that these proteins synergize in the activation of NF-kappaB. The data support a mechanism of action whereby Bcl10 mediates the oligomerization and activation of the MALT1 caspase-like domain. This subsequently activates the IKK complex through an unknown mechanism, setting in motion a cascade of events leading to NF-kappaB induction. Furthermore, the API2-MALT1 fusion protein also strongly activates NF-kappaB and shows dependence upon the same downstream signaling factors. We propose a model whereby both the Bcl10.MALT1 complex and the API2-MALT1 fusion protein activate a common downstream signaling pathway that originates with the oligomerization-dependent activation of the MALT1 caspase-like domain.

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    • "These include t[14;18] [q32;q21] involving IGH and MALT1, t[11;18] [q21;q21] involving API2 and MALT1, t[1;14] [p22;q32] involving Bcl-10 and IGH, and t[3;14] [p14;q32] involving FOXP1 and IGH [27]. All of these, except the translocation involving FOXP1, lead to formation or up-regulation of proteins (API2-MALT1, MALT1 and bcl-10) that ultimately target the NF-κBA20 gene by stimulating cell proliferation and survival [28] [29]. "
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    Journal of Cancer Therapy 03/2013; 4(02):662-677. DOI:10.4236/jct.2013.42082
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    • "CARMA1 forms part of the CARMA1-BCL10-MALT1 (CBM) complex and mediates NF-kB activation downstream of the B cell receptor, T cell receptor (Ruefli-Brasse et al., 2003; Ruland et al., 2003), and ITAM-coupled natural killer cell receptors (Gross et al., 2008). The MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) subunit is the active signaling component of the CBM complex (Lucas et al., 2001) and features protease activity that cleaves and inactivates inhibitors of the NF-kB signaling pathway such as TNFAIP3/A20 (Coornaert et al., 2008), CYLD (Staal et al., 2011), and RELB (Hailfinger et al., 2011) or the BCL10 protein (Rebeaud et al., 2008), indirectly activating NF-kB signaling. MALT1 translocations, including t(11;18)(q21;q21), which produces an API2-MALT1 "
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    Cancer cell 12/2012; 22(6):812-24. DOI:10.1016/j.ccr.2012.11.003 · 23.89 Impact Factor
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    • "Syndecan-2 is a cell surface heparan sulfate proteoglycan that is a co-receptor for IL8, thought to immobilize IL8 on the cell surface to mediate communication between endothelial cells and neutrophils in humans (Halden et al. 2004). The human Malt1 protein, when in complex with Bcl10, can activate NFκB (Lucas et al. 2001, 2004). Interestingly, Martin et al. (2009) found that the CBM complex, containing Carma3, Bcl10, and Malt1, was a key component of the activation of NFκB by IL8. "
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