ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Lewis, Juliana B.; Scangarello, Frank A; Murphy, Joanne M.; Eidell, Keith P.; Sodipo, Michelle O.; Ophir, Michael; Sargeant, R.; Seminario, Maria-Cristina; Bunnell, Stephen C.

doi:10.1242/jcs.215517

Cited by 17 publications

(32 citation statements)

References 83 publications

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“…SLP76 is composed of four key structures: an SH2 domain, a proline-rich region, a SAM domain, and an acidic domain containing three tyrosine phosphorylation sites (Y 113 , Y 128 , and Y 145 in humans) 43 , 45 . SLP76 was reported to function as a scaffold protein to form microclusters with Grap2, Vav1, and Nck, which were subsequently recruited to the membrane-proximal region by LAT to integrate signals for T-cell activation 46 . Despite the importance of SLP76 in T-cell immunity, the expression and function of SLP76 in macrophages are not well characterized.…”

Section: Discussionmentioning

confidence: 99%

Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

et al. 2021

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Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.

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Section: Discussionmentioning

confidence: 99%

Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

et al. 2021

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“…In the context of ADAP-trimerized SLP-76, these Gads-mediated interactions may contribute to the cross-linking of two or more LAT molecules (Figure 4, center), similar to the cross-linking induced by Grb2-SOS. Consistent with this notion, all three ADAP tyrosines are required for the optimal assembly and stabilization of TCR-induced microclusters (56); whereas any microclusters that form in the absence of ADAP are immobile, smaller, and less persistent than those seen in wild-type cells (55, 57).…”

Section: The Regulated Assembly and Disassembly Of Lat-nucleated Signmentioning

confidence: 75%

“…The SH2 domain of SLP-76 contributes to microcluster formation via its interaction with another adaptor protein known as ADAP (Figure 4, left). ADAP pre-localizes at TCR protrusions that may make contact with the APC (55). Upon TCR stimulation, ADAP is phosphorylated at three tyrosines that bind to SLP-76, resulting in the stable oligomerization of SLP-76 and its associated Gads (56).…”

Section: The Regulated Assembly and Disassembly Of Lat-nucleated Signmentioning

confidence: 99%

Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses

Yablonski

2019

Front. Immunol.

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Antigen receptor signaling pathways are organized by adaptor proteins. Three adaptors, LAT, Gads, and SLP-76, form a heterotrimeric complex that mediates signaling by the T cell antigen receptor (TCR) and by the mast cell high affinity receptor for IgE (FcεRI). In both pathways, antigen recognition triggers tyrosine phosphorylation of LAT and SLP-76. The recruitment of SLP-76 to phospho-LAT is bridged by Gads, a Grb2 family adaptor composed of two SH3 domains flanking a central SH2 domain and an unstructured linker region. The LAT-Gads-SLP-76 complex is further incorporated into larger microclusters that mediate antigen receptor signaling. Gads is positively regulated by dimerization, which promotes its cooperative binding to LAT. Negative regulation occurs via phosphorylation or caspase-mediated cleavage of the linker region of Gads. FcεRI-mediated mast cell activation is profoundly impaired in LAT- Gads- or SLP-76-deficient mice. Unexpectedly, the thymic developmental phenotype of Gads-deficient mice is much milder than the phenotype of LAT- or SLP-76-deficient mice. This distinction suggests that Gads is not absolutely required for TCR signaling, but may modulate its sensitivity, or regulate a particular branch of the TCR signaling pathway; indeed, the phenotypic similarity of Gads- and Itk-deficient mice suggests a functional connection between Gads and Itk. Additional Gads binding partners include costimulatory proteins such as CD28 and CD6, adaptors such as Shc, ubiquitin regulatory proteins such as USP8 and AMSH, and kinases such as HPK1 and BCR-ABL, but the functional implications of these interactions are not yet fully understood. No interacting proteins or function have been ascribed to the evolutionarily conserved N-terminal SH3 of Gads. Here we explore the biochemical and functional properties of Gads, and its role in regulating allergy, T cell development and T-cell mediated immunity.

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“…It can bind adaptor proteins Shc and Grb2, the p85 subunit of PI3K [86], SLP-76, Vav, and negative regulators such as SLAP [117], SLAP-2 [118,119], TRIM, CTLA4, and Unc119, as well as actin [113]. These proteins as well as GADS, phospholipase PLCγ1, Nck, p38 MAPK, and ADAP are recruited into a complex with linker for the activation of T cells (LAT) upon its phosphorylation by ZAP-70 [16,120,121].…”

Section: Tcr/p-mhc Ligationmentioning

confidence: 99%

“…Phosphorylated LAT binds additional adaptors GADS, GRB2, and phospholipase PLCγ1(NF-kB). This LAT complex subsequently recruits other adapters and enzymes, including SLP76, VAV1, Nck, p38 MAPK, and ADAP [16,120,121]. Phosphorylated ZAP-70 also has a noncatalytic function as a scaffold phosphoprotein that facilitates the high-affinity state of the integrin LFA-1, which in turn increases T cell adhesion by binding ICAM-1 on antigen-presenting cells [129].…”

Section: Tcr Coreceptorsmentioning

confidence: 99%

T Cell Reprogramming Against Cancer

Katz

Rabinovich

2019

Methods in Molecular Biology

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Advances in academic and clinical studies during the last several years have resulted in practical outcomes in adoptive immune therapy of cancer. Immune cells can be programmed with molecular modules that increase their therapeutic potency and specificity. It has become obvious that successful immunotherapy must take into account the full complexity of the immune system and, when possible, include the use of multifactor cell reprogramming that allows fast adjustment during the treatment. Today, practically all immune cells can be stably or transiently reprogrammed against cancer. Here, we review works related to T cell reprogramming, as the most developed field in immunotherapy. We discuss factors that determine the specific roles of αβ and γδ T cells in the immune system and the structure and function of T cell receptors in relation to other structures involved in T cell target recognition and immune response. We also discuss the aspects of T cell engineering, specifically the construction of synthetic T cell receptors (synTCRs) and chimeric antigen receptors (CARs) and the use of engineered T cells in integrative multifactor therapy of cancer.

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ADAP is an upstream regulator that precedes SLP-76 at sites of TCR engagement and stabilizes signaling microclusters

Cited by 17 publications

References 83 publications

Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis

Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses

T Cell Reprogramming Against Cancer

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