Distinct Regulation of Integrin-Dependent T Cell Conjugate Formation and NF-κB Activation by the Adapter Protein ADAP

Burbach, Brandon J.; Srivastava, Rupa; Medeiros, Ricardo B.; O’Gorman, William; Peterson, Erik; Shimizu, Yoji

doi:10.4049/jimmunol.181.7.4840

Cited by 26 publications

(77 citation statements)

References 63 publications

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“…However, a requirement for TAK1 in T cell receptor-mediated activation of NF-B appears to be dependent at least in part on the differentiation state of the T cell as NF-B activation is impaired in TAK1-deficient thymocytes and mature single-positive thymocytes but not in TAK1-deficient effector T cells (14,15). The expression system in this study utilized recombinant adenovirus and transgenic ADAP Ϫ/Ϫ mice expressing the hCAR receptor (20,21). Because this system allows for efficient transduction of primary, non-cycling naive T cells (22), our findings are consistent with a requirement for TAK1 in NF-B activation in naive T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Other primary antibodies were absorbed to GammaBind Plus Sepharose beads (GE Healthcare). Immunoprecipitates (IPs) were washed with 1ϫ lysis buffer prior to analysis by Western blotting as described previously (20,21). Membranes were imaged with an Odyssey infrared imager (LI-COR Biosciences).…”

Section: Mice-adapmentioning

confidence: 99%

“…Adenovirus Production and Transduction-Adenovirus expression plasmids and recombinant adenovirus were generated as described previously (20,21). ADAP mutants were generated using the QuikChange II XL site-directed mutagenesis kit (Stratagene) via the introduction of a stop codon at amino acid position 604 and 719 or by using primers flanking both sides of the deleted site (mutants ⌬673-686, ⌬621-672, ⌬691-708, and ⌬426 -541).…”

Section: Mice-adapmentioning

confidence: 99%

“…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. However, the precise mechanism by which ADAP controls IKK complex activation has not been elucidated.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Mice-adapmentioning

confidence: 99%

Section: Mice-adapmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Recent studies have established that PDK1 is critical for efficient activation of PKCθ in T cells and PKCβ in B cells by the PI3K pathway. PDK1 is also required for the subsequent assembly of the CBM complex to activate NF-κB during coordinated stimulation of the TCR and co-stimulatory receptor CD28 or during activation of the BCR [57][58][59]. PDK1 phosphorylates PKCθ and has a dual role in TCR-mediating NF-κB activation by recruiting PKCθ and CARMA1 into lipid rafts [60].…”

Section: Pkcθ and Pkcβmentioning

confidence: 99%

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

Messali¹,

Génin

Weil³

2013

J Leuk

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The adaptive immune response is initiated when microbial or tumor-specific molecules are recognized by antigen receptors present at lymphocyte cell surface. Engagement of these immunoreceptors induces signaling cascades that ultimately activate the transcription factors NF-κB (Nuclear Factor-κB) and NFAT (nuclear factor of activated T-cells) responsible for the establishment of gene expression programs controlling the stimulation, proliferation and survival of activated lymphocytes. Cloning the products of three distinct translocation events found in lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) led to the identification and characterization of a novel NF-κB-activating complex following antigenic stimulation composed by the CARMA1, BCL10, and MALT1 proteins and called the CBM complex. Since the identification of this complex, other regulatory components were discovered which greatly improve our understanding of this signaling pathways.Interestingly, CBM complex activity is not only altered in MALT lymphomas but also in a subtype of activated B cell-like (ABC) of diffuse large B-cell (DLBCL) lymphoma. In this review, we described the key players involved in antigen-induced NF-κB activation and covered the recent advances in the molecular mechanisms that are responsible for the regulation of the components of the CBM complex. Understanding these mechanisms is critical for the elucidation of the role of this NF-κB signaling network in both normal and pathologic conditions and we described how dysregulation of this network leads to the uncontrolled activation of NF-κB and development of two particular subtypes of human B cell lymphomas: the MALT and the DLBCL lymphomas. DAP12) [1]. Engagement of these receptors initiate a signal-activation cascade that includes phosphorylation of two specific tyrosine residues located in the ITAM by the Src family kinases [1]. Tyrosine kinase Syk or ZAP-70 (zeta-chain-associated protein 70 kD) are then recruited to the phosphorylated ITAM through their tandem Src homology 2 (SH2) regions, initiating downstream signaling cascades that lead to the stimulation of mitogen-activated protein kinase (MAPK) activities and ultimately to the activation of the transcription factors NF-κB and NF-AT (nuclear factor of activated T-cells).An outstanding issue of lymphocyte activation was the identification of a complex of proteins comprising CARMA1, BCL10 and MALT1 (also called the CBM complex) as critical regulators of the immunoreceptor signaling pathways. In this review, we will focus on the recent advances concerning the role of the CBM function in antigen-induced NF-κB signaling and detail how this pathway may selectively become dysregulated in lymphoma. The key players of antigen-mediated NF-κB activationAntigen receptor activation initiates a phosphorylation cascade that promotes assembly of the CBM signalosome complex composed of CARMA1, BCL10, and MALT1 that ultimately activates the NEMO/ IKK complex to promote NF-κB transcription (Figure 1). In this

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Overview of Integrin Signaling in the Immune System

Kinashi

2011

Methods in Molecular Biology

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It has been well established that integrins mediate cell-cell and cell-matrix adhesion and play crucial roles in the immune system such as leukocyte-endothelium interactions, immune synapse formation, and effector functions. Since the discovery that integrins undergo dynamic changes of adhesive activities in response to external stimuli, intensive studies have been conducted to elucidate the signaling events that control the activation of integrins (inside-out signaling) and signaling events from the induced integrin-dependent adhesion (outside-in signaling). The molecular characterization of these signaling pathways highlights the importance of integrins as bidirectional signaling receptors. The characteristics of integrin signaling are best exemplified in the immune system. This chapter highlights the recent studies of intracellular signaling pathways that regulate integrins in immunological contexts.

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Distinct Regulation of Integrin-Dependent T Cell Conjugate Formation and NF-κB Activation by the Adapter Protein ADAP

Cited by 26 publications

References 63 publications

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

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

Dysregulation of the antigen-induced NF-κB signaling pathway in the development of human B-cells lymphomas

Overview of Integrin Signaling in the Immune System

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