The Grb2 adaptor

Chardin, Pierre Teilhard de; Cussac, Didier; Maignan, S.; Ducruix, A.

doi:10.1016/0014-5793(95)00578-w

Cited by 125 publications

(122 citation statements)

References 53 publications

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“…Among them, the most frequently detected amino acid sequences were derived from Grb2. Grb2 is an adaptor protein constitutively associated with Sos, having two Src homology 3 (SH3) domain (N and C terminus) and one SH2 domain in the middle (21). Therefore, we next performed coimmunoprecipitation experiments using Flag-tagged Gasp and myc-tagged Grb2 and their mutants.…”

Section: Resultsmentioning

confidence: 99%

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Patrick

Oda²,

Hayakawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

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T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCRinduced events such as ␤-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocytespecific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection. (2). The fate of individual DP thymocytes is determined by the strength of affinity and longevity of interaction between their TCR and peptide:MHC ligand (3). Although it is known that strong TCR/ligand interaction leads to negative selection and weak association results in positive selection (4), how this quantitative difference of TCR interaction can be converted to the qualitative difference is not known. Therefore, it is important to investigate the difference in molecular mechanisms of positive and negative selection.

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Section: Resultsmentioning

confidence: 99%

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Patrick

Oda²,

Hayakawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Grb2 has been shown to play an essential role in several signal transduction pathways including the activation of p21 ras by growth factor receptors (for review see Chardin et al, 1995). The SH3 domainmediated Grb2/MPTP ± PEST complex may participate in growth factor receptor signalling cascades analogous to the p21 ras activation pathways.…”

Section: Resultsmentioning

confidence: 99%

Coupling of the murine protein tyrosine phosphatase PEST to the epidermal growth factor (EGF) receptor through a Src homology 3 (SH3) domain-mediated association with Grb2

et al. 1997

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The involvement of murine protein tyrosine phosphatase-PEST (MPTP ± PEST) in signal transduction pathways is suggested by its ability to dephosphorylate phosphotyrosine residues, its interaction with the adaptor protein SHC and by the presence of ®ve proline-rich stretches in its non-catalytic carboxyl terminus. Proline-rich sequences have been identi®ed as binding sites for Src homology 3 (SH3) domains found in proteins associated with signal transduction events. The ability of these sequences to act as SH3 domain recognition motifs was investigated using bacterially expressed SH3 domains derived from several di erent signalling proteins. In vitro binding assays indicate that four of these proline-rich sequences constitute speci®c binding sites for both SH3 domains of the adaptor molecule Grb2. Wild type Grb2, but not Grb2 proteins corresponding to loss-of-function mutants in the Caenorhabditis elegans sem-5 protein, associate with MPTP ± PEST in vivo. Experiments in EGF receptor expressing cells show that the interaction between MPTP ± PEST and Grb2 results in the binding of this complex to activated EGF receptors. In addition, identi®cation of putative substrate(s) of MPTP ± PEST have revealed a candidate protein of *120 kDa which is tyrosine phosphorylated upon EGF stimulation. Together, these results describe a novel SH3 domaindependent recruitment of a protein tyrosine phosphatase to an activated receptor tyrosine kinase and establish a potential role for MPTP ± PEST in signalling pathways at the molecular level.

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“…Indeed, βDG can bind Grb2, 29,41 the growth factor receptor bound adapter protein involved in the activation of several signaling pathways, including the recruitment to plasma membrane and subsequent activation of the Ras oncogene. 42 Thus, an excess of βDG might inhibit proliferation not only by a direct effect (i.e., activating inhibitory signals) but also by an indirect effect blocking or interfering with stimulatory signals (i.e., sequestering Grb2 and inhibiting activation of Grb2-dependent signaling pathways). Future studies looking at downstream molecules that mediate DG-dependent intracellular signaling pathways will be necessary to definitively assess the role(s) of DG complex on the regulation of cell growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells

Sgambato¹,

Camerini²,

Faraglia³

et al. 2004

Cancer Biology & Therapy

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Dystroglycan (DG) is an adhesion molecule formed by two subunits, α (extracellular) and β (transmembrane) DG, which are codified by a single gene and form a continuous link from the extracellular matrix to the intracellular cytoskeleton. Reduction or loss of expression of DG has been observed in human cancer cell lines and primary tumors and has been suggested to promote tumor development and invasiveness.In this study, the human breast epithelial non-tumorigenic MCF10F and the breast cancer MCF7 cell lines were engineered to stably express an exogenous DG cDNA and the effects on the phenotype of both cell lines were evaluated. The MCF10F transfected cells displayed an increased expression of both DG subunits which was associated with inhibition of the anchorage-dependent growth, accumulation of cells in the G 0 /G 1 phase of the cell cycle and increased adhesion to a substratum. The MCF7 transfected cells were unable to restore α-DG despite an increased expression of the β-DG subunit. Anchoragedependent and independent growth and the in vivo tumorigenicity were reduced in these derivatives that also displayed a reduced adhesion to a substratum and were shown to release α-DG in the culture medium.These findings confirm and extend previous evidence that transformation of mammary epithelial cells is associated with loss of their ability to retain α-DG on the cell membrane. Moreover, they indicate that DG is involved in cell functions other than cell adhesion to the extracellular matrix, and that its loss of function might predispose to tumor progression by compromising regulatory controls over cell growth and proliferation.

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The Grb2 adaptor

Cited by 125 publications

References 53 publications

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes

Coupling of the murine protein tyrosine phosphatase PEST to the epidermal growth factor (EGF) receptor through a Src homology 3 (SH3) domain-mediated association with Grb2

Increased expression of dystroglycan inhibits the growth and tumorigenicity of human mammary epithelial cells

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