CARMA1-mediated NF-kappaB and JNK activation in lymphocytes

Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Immunological Reviews (Impact Factor: 10.12). 04/2009; 228(1):199-211. DOI: 10.1111/j.1600-065X.2008.00749.x
Source: PubMed


Activation of transcription factor nuclear factor-kappaB (NF-kappaB) and Jun N-terminal kinase (JNK) play the pivotal roles in regulation of lymphocyte activation and proliferation. Deregulation of these signaling pathways leads to inappropriate immune response and contributes to the development of leukemia/lymphoma. The scaffold protein CARMA1 [caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1] has a central role in regulation of NF-kappaB and the JNK2/c-Jun complex in both B and T lymphocytes. During last several years, tremendous work has been done to reveal the mechanism by which CARMA1 and its signaling partners, B cell CLL-lymphoma 10 and mucosa-associated lymphoid tissue 1, are activated and mediate NF-kappaB and JNK activation. In this review, we summarize our findings in revealing the roles of CARMA1 in the NF-kappaB and JNK signaling pathways in the context of recent advances in this field.

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Available from: Marzenna Blonska
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    • "PKCθ phosphorylates CARMA1 in its Linker between the CD-CC domain and the MAGUK domain, which induces conformational change of CARMA1 [7], [8]. Then CARMA1 binds to Bcl10 through CARD-CARD interaction [9], [36]. Since our data suggested that CKIP-1 interacted with the CC domain of CARMA1, we hypothesized that CKIP-1 might inhibit the interaction between CARMA1 and PKCθ or between CARMA1 and Bcl10. "
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    ABSTRACT: The transcription factor NF-κB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCθ, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF-κB activation. While many molecular events leading to NF-κB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR-mediated NF-κB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCθ-CBM-NF-κB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCθ for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-κB activity in unstimulated cells, and inhibits NF-κB activation induced by stimulation with PMA or constitutively active PKCθ, but not by stimulation with TNFα. Interestingly, CKIP-1 does not inhibit NF-κB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-κB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCθ-CBM-NF-κB signaling.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "For example, the MAGUK-containing CARMA1 emerges as a central regulator of lymphocytes activation and proliferation downstream of antigen receptor stimulation [14]. Indeed, CARMA1 operates as scaffold to recruit the heterodimer BCL10/MALT1 (CBM complex), a key step for conveying NF-κB signaling [14], [15], [16]. In addition to its established role in polarity, Dlgh1 was shown to modulate lymphocyte proliferation upon T-cell receptor ligation, possibly through p38 recruitment or via the transcription factor NF-AT [9], [10], [17], [18]. "
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    ABSTRACT: Beside their established function in shaping cell architecture, some cell polarity proteins were proposed to participate to lymphocyte migration, homing, scanning, as well as activation following antigen receptor stimulation. Although PALS1 is a central component of the cell polarity network, its expression and function in lymphocytes remains unknown. Here we investigated whether PALS1 is present in T cells and whether it contributes to T Cell-Receptor (TCR)-mediated activation. By combining RT-PCR and immunoblot assays, we found that PALS1 is constitutively expressed in human T lymphocytes as well as in Jurkat T cells. siRNA-based knockdown of PALS1 hampered TCR-induced activation and optimal proliferation of lymphocyte. We further provide evidence that PALS1 depletion selectively hindered TCR-driven activation of the transcription factor NF-κB. The cell polarity protein PALS1 is expressed in T lymphocytes and participates to the optimal activation of NF-κB following TCR stimulation.
    Full-text · Article · Mar 2011 · PLoS ONE
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    • "Further studies will be required to understand how the multiple domains of GAKIN integrate function prior to and during antigen receptor signaling. Bcl10 is an obligate component of the TCR pathway (Ruland et al., 2001), and its recruitment to CARD11 is an essential step in TCR signaling (Blonska and Lin, 2009). The dynamic association of GAKIN with CARD11 appears to reduce the fraction of CARD11 molecules that associate with Bcl10 during signaling (Figures 3I and 3J). "
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    ABSTRACT: T cell receptor (TCR) signaling to NF-κB is required for antigen-induced T cell activation. We conducted an expression-cloning screen for modifiers of CARD11, a critical adaptor in antigen receptor signaling, and identified the kinesin-3 family member GAKIN as a CARD11 inhibitor. GAKIN negatively regulates TCR signaling to NF-κB, associates with CARD11 in a signal-dependent manner and can compete with the required signaling protein, Bcl10, for association. In addition, GAKIN dynamically localizes to the immunological synapse and regulates the redistribution of CARD11 from the central region of the synapse to a distal region. We propose that CARD11 scaffold function and occupancy at the center of the synapse are negatively regulated by GAKIN to tune the output of antigen-receptor signaling.
    Full-text · Article · Dec 2010 · Molecular cell
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