Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

Hailfinger, Stephan; Lenz, Georg; Ngo, Vu N.; Posvitz-Fejfar, Anita; Rebeaud, Fabien; Guzzardi, Montserrat; Penas, Eva-Maria Murga; Dierlamm, Judith; Chan, Wing C.; Staudt, Louis M.; Thome, Margot

doi:10.1073/pnas.0907511106

Cited by 187 publications

(227 citation statements)

References 34 publications

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“…4A). Congruent with the previously observed constitutive cleavage of the MALT1 substrates BCL10 and A20 in ABC DLBCL cells (8,9), we found increased constitutive MALT1 activity in all ABC DLBCL cell lines compared with three GCB DLBCL cell lines, despite comparable amounts of MALT1 in the different DLBCL cells (8). Similar to the recombinant GST-MALT1 protease, cellular MALT1 activity was completely blocked by the addition of 50 nM Z-VRPR-FMK to the cleavage reaction (Fig.…”

Section: Pi3k-pdk1 Signaling Controls Viability Of a Subset Of Abc DLmentioning

confidence: 50%

“…The MALT1 protein encodes for a mammalian cystein protease that can cleave BCL10 and A20 and is activated in T cells or ABC DLBCL cells (5-9). MALT1 inhibition is toxic to ABC DLBCL cells (8,9). To examine whether PI3K activity could control constitutive MALT1 activity, we first conducted an assay to measure cellular MALT1 protease activity (Fig.…”

Section: Pi3k-pdk1 Signaling Controls Viability Of a Subset Of Abc DLmentioning

confidence: 99%

“…Constitutive anti-apoptotic and pro-proliferative NF-κB activity via the CARMA1-BCL10-MALT1 (CBM) complex is a characteristic of the activated B-cell-like (ABC) subtype of DLBCL that constitutes an aggressive lymphoma entity (2)(3)(4). MALT1 encodes for a cystein protease whose activity is required for optimal T-cell activation (5-7) as well as survival of ABC DLBCL cells (8,9). Distinct molecular aberrations have been suggested to contribute to pathological activation of the CBM complex in ABC DLBCL cells.…”

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confidence: 99%

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Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

Kloo

Nagel

Pfeifer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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131

116

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The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Constitutive NF-κB activation caused by chronic active B-cell receptor (BCR) signaling is common feature of many ABC DLBCL cells; however, the pathways linking BCR signaling to the NF-κB prosurvival network are largely unknown. Here we report that constitutive activity of PI3K and the downstream kinase PDK1 are essential for the viability of two ABC DLBCL cell lines that carry mutations in the BCR proximal signaling adaptor CD79B. In these cells, PI3K inhibition reduces NF-κB activity and decreases the expression of NF-κB target genes. Furthermore, PI3K and PDK1 are required for maintaining MALT1 protease activity, which promotes survival of the affected ABC DLBCL cells. These results demonstrate a critical function of PI3K-PDK1 signaling upstream of MALT1 protease and NF-κB in distinct ABC DLBCL cells and provide a rationale for the pharmacologic use of PI3K inhibitors in DLBCL therapy.

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Section: Pi3k-pdk1 Signaling Controls Viability Of a Subset Of Abc DLmentioning

confidence: 50%

Section: Pi3k-pdk1 Signaling Controls Viability Of a Subset Of Abc DLmentioning

confidence: 99%

mentioning

confidence: 99%

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Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

Kloo

Nagel

Pfeifer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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131

116

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“…Screening of patient samples performed independently by three groups has revealed that CARMA1 is mutated in about 10% of systemic ABC-DLBCL and 16% of primary central nervous system DLBCL [115][116][117]. The oncogenic mutant of CARMA1 constitutively recruits downstream signaling components [118], and likely induces proteolytic activity of MALT1 [119,120], leading to activation of NF-κB [115].…”

Section: The Role Of Cbm Proteins In Lymphomamentioning

confidence: 99%

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

Blonska¹,

Lin²

2010

Cell Res

176

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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“…4d-i, -ii, -iii). Overexpression of API2-MALT1C464A slightly decreased L428 cell proliferation and colony formation, which may be due to the dominant negative effect that inhibits the endogenous activity of MALT1 in B lymphoma cells 20,45 . Interestingly, we observed that L428 cells expressing API2-MALT1 proliferated much faster than the LIMA1a-depleted L428 cells ( Fig.…”

Section: Lima1a Silencing or Cleavage Inhibits Tumour Suppressionmentioning

confidence: 99%

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

Nie

McAllister-Lucas

et al. 2015

Nat Commun

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MALT1 is the only known paracaspase and is a critical mediator of B-and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.

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Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma

Cited by 187 publications

References 34 publications

Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

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

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma

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