Regulation of NF-κB Activation in T Cells via Association of the Adapter Proteins ADAP and CARMA1

Medeiros, Ricardo B.; Burbach, Brandon J.; Mueller, Kristen L.; Srivastava, Rupa; Moon, James; Highfill, Sarah; Peterson, Erik; Shimizu, Yoji

doi:10.1126/science.1137895

Cited by 91 publications

(164 citation statements)

References 27 publications

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“…The second step for CAR-MA1 recruitment to the immunological synapse seems to be dependent on its inducible interaction with an adaptor protein known as ADAP (adhesion-and degranulationpromoting adapter protein). Upon TCR engagement, ADAP and CARMA1 are recruited into the immunological synapse, and ADAP deficiency results in impaired CARMA1 translocation leading to reduced NF-κB activation [63]. However, ADAP is not a membrane protein and it is unlikely that ADAP anchors the MAGUK domain of CARMA1 to the cytoplasmic membrane.…”

Section: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

“…Mutation of Ser109 to Ala residue in CARMA1 impairs its biological function [72]. Once activated, CARMA1 recruits the IKK complex [60,61] and other signaling molecules (Table 1) [63,[67][68][69]73], including Bcl10 and its pre-associated partner MALT1 [60,61,74]. TCR-induced formation of the CARMA1-Bcl10-MALT1 complex is critical for IKK activation.…”

Section: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

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

Blonska¹,

Lin²

2010

Cell Res

173

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: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

Section: The Mechanism Of T Cell Receptor-induced Car-ma1 Activationmentioning

confidence: 99%

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

Blonska¹,

Lin²

2010

Cell Res

173

201

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“…Ϫ/Ϫ mice and ADAP Ϫ/Ϫ mice crossed to hCAR transgenic mice (22) on the BALB/c background have been previously described (20). Mice were housed in specific pathogenfree facilities at the University of Minnesota and were used between 8 and 10 weeks of age.…”

Section: Mice-adapmentioning

confidence: 99%

“…We previously identified a novel function for ADAP in controlling NF-B activation via regulation of CBM complex assembly (20). A region of ADAP between amino acids 426 and 541 mediates the association of ADAP with CARMA1, and a mutant of ADAP lacking this site is unable to restore NF-B activation in ADAP Ϫ/Ϫ T cells (20). This mutant can restore integrin function in ADAP Ϫ/Ϫ T cells (21), indicating that ADAP independently controls integrin function and NF-B activation.…”

mentioning

confidence: 99%

NF-κB Activation in T Cells Requires Discrete Control of IκB Kinase α/β (IKKα/β) Phosphorylation and IKKγ Ubiquitination by the ADAP Adapter Protein

Srivastava

Burbach²,

Shimizu

2010

Journal of Biological Chemistry

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NF-B activation following engagement of the antigen-specific T cell receptor involves protein kinase C--dependent assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, which coordinates downstream activation of IB kinase (IKK).We previously identified a novel role for the adhesion-and degranulation-promoting adapter protein (ADAP) in regulating the assembly of the CBM complex via an interaction of ADAP with CARMA1. In this study, we identify a novel site in ADAP that is critical for association with the TAK1 kinase. ADAP is critical for recruitment of TAK1 and the CBM complex, but not IKK, to protein kinase C-. ADAP is not required for TAK1 activation. Although both the TAK1 and the CARMA1 binding sites in ADAP are essential for IB␣ phosphorylation and degradation and NF-B nuclear translocation, only the TAK1 binding site in ADAP is necessary for IKK phosphorylation. In contrast, only the CARMA1 binding site in ADAP is required for ubiquitination of IKK␥. Thus, distinct sites within ADAP control two key activation responses that are required for NF-B activation in T cells.In the immune system, the NF-B transcription factor pathway plays a central role in T cell activation and survival (1, 2). The canonical NF-B pathway involves activation of the IBkinase (IKK) 3 complex, which consists of the catalytic IKK␣ and IKK␤ subunits and the regulatory IKK␥ (NF-B essential modulator (NEMO)) subunit. Activated IKK mediates phosphorylation of IB␣, resulting in IB␣ degradation and translocation of NF-B to the nucleus. In T cells, stimulation of the T cell receptor and the CD28 co-stimulatory receptor results in activation of the PKC isoform and association of the IKK complex with PKC (3). PKC phosphorylates the membrane-associated guanylate kinase (MAGUK) family member adapter CARMA1 (4, 5), which then associates with the adapters BCL-10 and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (6, 7). Activation of the IKK complex is proposed to require both Lys-63-linked ubiquitination of IKK␥ (8, 9) and IKK␣/␤ phosphorylation (10). Recent studies suggest that IKK␥ ubiquitination is dependent on efficient CBM complex formation, whereas phosphorylation of IKK␣/␤ is mediated by TGF␤-activated kinase (TAK1) (11). Both of these regulatory events appear to be required for efficient NF-B activation as loss of expression of CARMA1, BCL-10, MALT1, or TAK1 results in impaired NF-B signaling in T cells (7,(12)(13)(14)(15). The mechanism by which TAK1 is recruited to the PKC signalosome is unclear. Although CARMA1 and TAK1 have been reported to associate with each other (11,16,17), TAK1-mediated IKK␣/␤ phosphorylation is intact in CARMA1-deficient Jurkat T cells (11). This suggests that IKK␥ ubiquitination and IKK␣/␤ phosphorylation are independently controlled.Adhesion-and degranulation-promoting adapter protein (ADAP) is a hematopoietic-specific adapter protein that regulates "inside-out" signaling from the T cell receptor to integrins (18,19). We previously identified a novel function for ADAP in controlling ...

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“…1C-E) whereas ADAP expression is restricted to T and myeloid cells (42). Further studies are needed to determine the biological significance of ARAP for integrin activation in distinct cell types and to clarify the difference in upstream and downstream signaling pathways for ARAP and ADAP in T cells.…”

Section: Discussionmentioning

confidence: 99%

ARAP, a Novel Adaptor Protein, Is Required for TCR Signaling and Integrin-Mediated Adhesion

Jung

Yoo

et al. 2016

The Journal of Immunology

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A novel adaptor protein was identified by analyzing phosphotyrosine proteomes from membrane rafts of activated T cells. This protein showed sequence similarity to a well-known T cell adaptor protein, adhesion and degranulation-promoting adaptor protein (ADAP); therefore, the novel protein was designated activation-dependent, raft-recruited ADAP-like phosphoprotein (ARAP). Suppression of ARAP impaired the major signaling pathways downstream of the TCR. ARAP associated with the Src homology 2 domain of Src homology 2–containing leukocyte protein of 76 kDa via the phosphorylation of two YDDV motifs in response to TCR stimulation. ARAP also mediated integrin activation but was not involved in actin polymerization. The results of this study indicate that a novel T cell adaptor protein, ARAP, plays a unique role in T cells as a part of both the proximal activation signaling and inside–out signaling pathways that result in integrin activation and T cell adhesion.

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Regulation of NF-κB Activation in T Cells via Association of the Adapter Proteins ADAP and CARMA1

Cited by 91 publications

References 27 publications

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

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

NF-κB Activation in T Cells Requires Discrete Control of IκB Kinase α/β (IKKα/β) Phosphorylation and IKKγ Ubiquitination by the ADAP Adapter Protein

ARAP, a Novel Adaptor Protein, Is Required for TCR Signaling and Integrin-Mediated Adhesion

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