Disease relevance of Bcl10

• We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling [1].
• Bcl10 expressed in a MALT lymphoma exhibited a frameshift mutation resulting in truncation distal to the CARD [2].
• Bcl10 is a cellular homolog of the equine herpesvirus-2 E10 gene: both contain an amino-terminal caspase recruitment domain (CARD) homologous to that found in several apoptotic molecules [2].

High impact information on Bcl10

• Thus, Bcl10 functions as a positive regulator of lymphocyte proliferation that specifically connects antigen receptor signaling in B and T cells to NF-kappaB activation [3].
• Bcl10, a CARD-containing protein identified from the t(1;14)(p22;q32) breakpoint in MALT lymphomas, has been shown to induce apoptosis and activate NF-kappaB in vitro [3].
• However, surviving bcl10-/- mice were severely immunodeficient and bcl10-/- lymphocytes are defective in antigen receptor or PMA/Ionomycin-induced activation [3].
• Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types [2].
• Truncated Bcl10 activated NF-kappaB but did not induce apoptosis [2].

Biological context of Bcl10

• The defect in Rip2-/- T-cells correlated with a lack of TCR-induced Bcl10 phosphorylation [4].
• Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein [5].
• NKT cells, on the other hand, require PKCtheta for thymic development, whereas absence of Bcl10 leads primarily to the reduction of peripheral NKT cell numbers [6].
• Bcl10 downregulation is not affected by proteasome inhibitors but is accompanied by transient localization to lysosomal vesicles, suggesting involvement of the lysosomal pathway rather than the proteasome [7].
• Through activation of NF-kappaB, v-CARMEN may regulate the expression of the cellular and viral genes important for viral replication [8].

Anatomical context of Bcl10

• In contrast to Bcl10 disruption, however, inactivation of Malt1 has only mild effects on B cell activation and does not cause defects during neurodevelopment [9].
• Bcl10 is an intracellular protein essential for nuclear factor (NF)-kappaB activation after lymphocyte antigen receptor stimulation [10].
• These findings also uncover a function of the CARMA, Bcl10, and MALT1 proteins in cells outside the immune system [11].
• TCR activation causes enrichment of PKC at the c-SMAC, followed by Bcl10 relocalization to punctate cytoplasmic structures, often at sites distant from the c-SMAC [12].
• Synchronized HCT116 3-6 cells treated with a low dose of FdUrd had a 2-fold greater G(2) cell cycle arrest compared with MMR-deficient HCT116 cells, and asynchronous ME-10 cells demonstrated a 4-fold greater G(2) arrest after FdUrd treatment compared with CT-5 cells [13].

Associations of Bcl10 with chemical compounds

• However, both Bcl10-deficient follicular and marginal zone B cells failed to proliferate normally, although Bcl10-deficient marginal zone B cells uniquely failed to activate NF-kappaB efficiently after stimulation with lipopolysaccharide [10].
• In addition, Bcl10(-/-) mice show defective hepatic cytokine production after Ang II treatment [11].
• CARMA3/Bcl10/MALT1-dependent NF-{kappa}B activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells [11].
• Bcl10 and Malt1 control lysophosphatidic acid-induced NF-{kappa}B activation and cytokine production [14].
• Although Bcl10-deficient mast cells have normal de novo synthesis and release of the lipid mediator arachidonic acid, the mutant cells possess impaired FcepsilonR-mediated degranulation, indicated by decreased serotonin release, and impaired cytokine production, measured by release of IL-6 [15].

Physical interactions of Bcl10

• Although the paracaspase MALT1 can bind to BCL10, the physiological function of MALT1 is unknown [9].
• The recruitment of BCL10 to TLR4 signaling complexes was attenuated by induced expression of SOCS3 in a feedback loop [16].

Other interactions of Bcl10

• The Bcl10-Malt1 complex segregates Fc epsilon RI-mediated nuclear factor kappa B activation and cytokine production from mast cell degranulation [1].
• Antigen receptor-mediated activation of NF-kappa B, required for proliferation of B and T cells, is disrupted in T cells lacking PKC theta and in B and T cells lacking Bcl10, a caspase recruitment domain (CARD)-containing adaptor protein [17].
• We demonstrate that there is a surprisingly complex relocalization process that brings PKC and Bcl10, two intermediates in TCR activation of NF-kappaB, to the cytoplasmic face of the c-SMAC [12].
• BCL10 mediates lipopolysaccharide/toll-like receptor-4 signaling through interaction with Pellino2 [16].
• Herein, we demonstrate that BCL10, a critical molecule that signals between the T cell receptor and IkappaB kinase complexes, is involved in the innate immune system and is required for appropriate TLR4 pathway and nuclear factor-kappaB (NF-kappaB) activation [16].

Analytical, diagnostic and therapeutic context of Bcl10

• In peripheral T cells, TCR ligation activates NF-kappaB through a selective pathway that involves protein kinase Ctheta, Bcl10, and Malt1 [18].

References