Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc

Sk, Liu; Cj, McGlade

doi:10.1038/sj.onc.1202337

Cited by 107 publications

(109 citation statements)

References 29 publications

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“…During the preparation of this study for publication, sequences identical with GRID were independently reported by a number of other groups (26,33,34,51,52). These reports confirm our finding that GRID is primarily expressed in T lymphocytes.…”

Section: Cloning Of a Novel Cd28 Binding Proteinsupporting

confidence: 90%

“…Several of the reported GRID interacting proteins possess phosphotyrosine motifs that meet the Grb2 consensus, including CD28 (pYMNM) (the present study), Fms (pYKNI) (52), p66Shc (pYYND and pYVNV) (26), and LAT (pYVNV) (34,53), suggesting that the SH2 recognition motif of GRID and that of Grb2 have broadly similar binding specificities. In our initial experimental analysis of GRID's SH2 domain recognition properties, we found that mutation of the asparagine residue (N175) in the CD28 cytoplasmic domain abolishes GRID binding, whereas alterations at the preceding residue, Met 174 , have no effect, as predicted by the consensus.…”

Section: Specificity Within the Grb2 Familysupporting

confidence: 54%

“…During preparation of this work, a number of other workers have deposited sequences identical with GRID in the GenBank database: GrbX, accession number AF090456; GrbLG, AJ011736; Grf40, AF042380; Gads, Y18051; and Grap-2, AF102694 (26,33,34). Comparison of these cDNA sequences identifies a number of conservative point mutations in the coding sequence.…”

Section: Lckmentioning

confidence: 99%

“…In one such cell line, p62 dok is constitutively phosphorylated due to the activity of p210 bcr/abl , even though it does not interact directly with the PTK (58). GRID has been shown to bind autophosphorylated p210 bcr/abl and also to be expressed at high levels in another CML line (26), suggesting that in CML cells as well as T cells, GRID may serve as a bridge to recruit p62 dok to an activating PTK environment. Secondly, GRID has recently been reported to associate with LAT (linker for T cell activation, previously known as pp36) following activation of the T cells via cross-linking of the TCR (34,53).…”

Section: What Is the Role Of Grid In T Cells?mentioning

confidence: 99%

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GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28

Ellis¹,

Ashman²,

Burden³

et al. 2000

The Journal of Immunology

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Adapter proteins such as Grb2 play a central role in the formation of signaling complexes through their association with multiple protein binding partners. These interactions are mediated by specialized domains such as the well-characterized Src homology SH2 and SH3 motifs. Using yeast three-hybrid technology, we have identified a novel adapter protein, expressed predominantly in T lymphocytes, that associates with the activated form of the costimulatory receptor, CD28. The protein is a member of the Grb2 family of adapter proteins and contains an SH3-SH2-SH3 domain structure. A unique glutamine/proline-rich domain (insert domain) of unknown function is situated between the SH2 and N-terminal SH3 domains. We term this protein GRID for Grb2-related protein with insert domain. GRID coimmunoprecipitates with CD28 from Jurkat cell lysates following activation of CD28. Using mutants of CD28 and GRID, we demonstrate that interaction between the proteins is dependent on phosphorylation of CD28 at tyrosine 173 and integrity of the GRID SH2 domain, although there are also subsidiary stabilizing contacts between the PXXP motifs of CD28 and the GRID C-terminal SH3 domain. In addition to CD28, GRID interacts with a number of other T cell signaling proteins, including SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa), p62dok, and RACK-1 (receptor for activated protein kinase C-1). These findings suggest that GRID functions as an adapter protein in the CD28-mediated costimulatory pathway in T cells.

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Section: Cloning Of a Novel Cd28 Binding Proteinsupporting

confidence: 90%

Section: Specificity Within the Grb2 Familysupporting

confidence: 54%

Section: Lckmentioning

confidence: 99%

Section: What Is the Role Of Grid In T Cells?mentioning

confidence: 99%

See 2 more Smart Citations

GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28

Ellis¹,

Ashman²,

Burden³

et al. 2000

The Journal of Immunology

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show abstract

“…It probably has many redundant functions in T cells and also competes with its relatives for binding sites as a result of its close homology with other proteins of the Grb2 family of adapter proteins (43,44). Therefore, the effects of Grb2 deletion in T cells may be milder than expected for such an important signaling protein.…”

Section: Discussionmentioning

confidence: 99%

Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis

Radtke

Lacher

Szumilas

et al. 2016

The Journal of Immunology

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The small adaptor protein growth factor receptor–bound protein 2 (Grb2) modulates and integrates signals from receptors on cellular surfaces in inner signaling pathways. In murine T cells, Grb2 is crucial for amplification of TCR signaling. T cell–specific Grb2fl/fl Lckcretg Grb2-deficient mice show reduced T cell numbers due to impaired negative and positive selection. In this study, we found that T cell numbers in Grb2fl/fl CD4cretg mice were normal in the thymus and were only slightly affected in the periphery. Ex vivo analysis of CD4+ Th cell populations revealed an increased amount of Th1 cells within the CD4+ population of Grb2fl/fl CD4cretg mice. Additionally, Grb2-deficient T cells showed a greater potential to differentiate into Th17 cells in vitro. To test whether these changes in Th cell differentiation potential rendered Grb2fl/fl CD4cretg mice more prone to inflammatory diseases, we used the murine Th1 cell– and Th17 cell–driven model of experimental autoimmune encephalomyelitis (EAE). In contrast to our expectations, Grb2fl/fl CD4cretg mice developed a milder form of EAE. The impaired EAE disease can be explained by the reduced proliferation rate of Grb2-deficient CD4+ T cells upon stimulation with IL-2 or upon activation by allogeneic dendritic cells, because the activation of T cells by dendritic cells and the subsequent T cell proliferation are known to be crucial factors for the induction of EAE. In summary, Grb2-deficient T cells show defects in T cell development, increased Th1 and Th17 cell differentiation capacities, and impaired proliferation after activation by dendritic cells, which likely reduce the clinical symptoms of EAE.

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SH3 Domains as Drug Targets

Luccarelli

Thompson

Hamilton

2013

Methods and Principles in Medicinal Chemistry

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Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc

Cited by 107 publications

References 29 publications

GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28

GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28

Grb2 Is Important for T Cell Development, Th Cell Differentiation, and Induction of Experimental Autoimmune Encephalomyelitis

SH3 Domains as Drug Targets

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