Selective Expansion of Marginal Zone B Cells in Eμ-API2-MALT1 Mice Is Linked to Enhanced IκB Kinase γ Polyubiquitination

Baens, Mathijs; Fevery, Sabine; Sagaert, Xavier; Noels, Heidi; Hagens, Sofie; Broeckx, Vicky; Billiau, An; Wolf-Peeters, Christiane De; Marynen, Peter

doi:10.1158/0008-5472.can-05-4590

Cited by 62 publications

(59 citation statements)

References 37 publications

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“…Although transient transfection of wild type MALT1 does not significantly activate NF-κB, overexpression of its oncogenic form potently activates NF-κB in vitro [42,45]. Consistent with these results, transgenic mice expressing Eµ-API2-MALT1 have elevated NF-κB activity [46]. On the other hand, genetic inactivation of Malt1 gene in mice impairs TCR-induced NF-κB activation [47,48].…”

Section: Cbm Proteins In Antigen Receptor Signalingmentioning

confidence: 64%

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Blonska¹,

Lin²

2010

Cell Res

174

201

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The NF-κB family of transcription factors plays a crucial role in cell activation, survival and proliferation. Its aberrant activity results in cancer, immunodeficiency or autoimmune disorders. Over the past two decades, tremendous progress has been made in our understanding of the signals that regulate NF-κB activation, especially how scaffold proteins link different receptors to the NF-κB-activating complex, the IκB kinase complex. The growing number of these scaffolds underscores the complexity of the signaling networks in different cell types. In this review, we discuss the role of scaffold molecules in signaling cascades induced by stimulation of antigen receptors, G-protein-coupled receptors and C-type Lectin receptors, resulting in NF-κB activation. Especially, we focus on the family of Caspase recruitment domain (CARD)-containing proteins known as CARMA and their function in activation of NF-κB, as well as the link of these scaffolds to the development of various neoplastic diseases through regulation of NF-κB.

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Section: Cbm Proteins In Antigen Receptor Signalingmentioning

confidence: 64%

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

Blonska¹,

Lin²

2010

Cell Res

174

201

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“…In addition to disrupting TRAF2 binding and/or oligomerization, deletions or mutations of the BIR1 domain might also disrupt other vital functions of the API2 moiety of API2-MALT1. For example, a recent report suggested that the BIR1 domain of API2 might contribute to API2-MALT1-dependent NF-kB activation by promoting association of the fusion protein with membrane lipid rafts (Baens et al, 2006). Another recent report demonstrated that the API2 BIR1 interacts with Bcl10 (Hu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

Lucas

Kuffa

et al. 2007

Oncogene

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Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extranodal lymphoid neoplasm. Chromosomal translocation t(11;18)(q21,q21) is found in 30% of gastric MALT lymphomas and is associated with a failure to respond to standard treatment and a tendency to disseminate. This translocation generates a chimeric protein composed of N-terminal sequences of Inhibitor of Apoptosis 2 (API2, also known as BIRC3 and cIAP2) fused to C-terminal sequences of MALT1. API2-MALT1 promotes cell survival and proliferation via activation of nuclear factor-jB (NF-jB). Here, we investigate the mechanism by which the API2 moiety contributes to NF-jB stimulation. We find that the API2 moiety mediates oligomerization of API2-MALT1 as well as interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2). Surprisingly, oligomerization does not occur via homotypic interaction; rather, the API2 moiety of one monomer interacts with the MALT1 moiety of another monomer. Further, the specific region of the API2 moiety responsible for mediating oligomerization is distinct from that mediating TRAF2 binding. Although deletion or mutation of the TRAF2 binding site does not inhibit oligomerization, it does lead to dramatically decreased NF-jB activation. Deletion of both TRAF2 binding and oligomerization regions results in nearcomplete loss of NF-jB activation. Thus, API2 moietymediated heterotypic oligomerization and TRAF2 binding both contribute to maximal API2-MALT1-dependent NF-jB stimulation.

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“…In fact, targeting the MALT1 C-terminus to the rafts appeared to be sufficient to activate NF-kB. 55 Likewise, permanent raft association of the fusion protein in splenic lymphocytes from API2-MALT1 transgenic mice and of API2-MALT1-expressing BJAB B cells was associated with increased polyubiquitination of IKKg and NF-kB activity respectively. 55,56 Raft association might facilitate oligomerization of the API2-MALT1 fusion protein and/or the interaction of its MALT1 domains with downstream signaling components like TRAF6, in this way bypassing the normal antigen requirement for formation of MALT1-TRAF6 oligomers and resulting in constitutive NF-kB activation.…”

Section: Pathogenesis Of Malt Lymphomasmentioning

confidence: 99%

“…A role for TRAF6 is supported by the finding that an API2-MALT1 fusion lacking the C-terminal TRAF6 binding site still resided in the lipid rafts, though it was incompetent to activate NF-kB. 55 On the other hand, a recent study questioned a role for TRAF6 in NF-kB activation by API2-MALT1, 51 which warrants further studies.…”

Section: Pathogenesis Of Malt Lymphomasmentioning

confidence: 99%

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The pathogenesis of MALT lymphomas: where do we stand?

et al. 2007

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Mucosa-associated lymphoid tissue (MALT) lymphoma is a heterogeneous form of a B-cell non-Hodgkin's lymphoma with extranodal location. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been documented. Four translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32), are specifically associated with MALT lymphoma. Remarkably, the genes targeted by at least three of these translocations are involved in one and the same pathway, leading to the activation of nuclear factor-jB (NF-jB). This review presents MALT lymphoma as a model of how sustained inflammation increases the risk of genotoxic insults and how these genetic events initiate oncogenesis.

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Selective Expansion of Marginal Zone B Cells in Eμ-API2-MALT1 Mice Is Linked to Enhanced IκB Kinase γ Polyubiquitination

Cited by 62 publications

References 37 publications

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

The pathogenesis of MALT lymphomas: where do we stand?

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