Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection

Johnson, Andrew L.; Aravind, L.; Shulzhenko, Natalia; Morgun, Andriy; Choi, Seeyoung; Crockford, Tanya L.; Lambe, Teresa; Domaschenz, Heather; Kucharska, Edyta M.; Zheng, Lixin; Vinuesa, Carola G.; Goodnow, Christopher C.; Cornall, Richard J.; Schwartz, Ronald H.

doi:10.1038/ni.1769

Cited by 114 publications

(197 citation statements)

References 46 publications

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“…Despite the absence of strong biochemical evidence, it was presumed that Themis1 likely functions as a positive regulator of TCR signaling because several defects in Themis1 −/− mice, such as a marked impairment of both positive and negative selection, were consistent with a deficiency in TCR signaling (2)(3)(4)(5)(6). It was subsequently shown that Themis1 interacts with Vav1 and that Vav1 phosphorylation is reduced in Themis1 −/− thymocytes, results that also implied a positive role for Themis1 in TCR signaling (9).…”

Section: Discussionmentioning

confidence: 99%

“…We and others identified the previously uncharacterized protein Themis1 as being required for the positive selection and maturation of T cells in the thymus (2)(3)(4)(5)(6). Themis1 lacks any discernable catalytic domain, but it contains two previously uncharacterized cysteine-based globular domains (named "CABIT") of unknown structure and function (3).…”

Section: Introductionmentioning

confidence: 99%

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Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain-containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1 −/− mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

et al. 2016

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“…These data suggest either functional redundancy via Sos2 or that additional, Sos-independent, signaling proteins may transduce signals downstream of Grb2 at the DP stage. One such candidate is Themis, a recently identified Grb2-interacting, T-cell-specific gene required for positive and negative selection (49)(50)(51). Similar to Grb2 −/− mice, Themis −/− mice showed defective negative selection in HY + male mice and following SEB injection (51).…”

Section: Discussionmentioning

confidence: 99%

Targeted Sos1 deletion reveals its critical role in early T-cell development

Kortum¹,

Sommers²,

Alexander³

et al. 2011

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

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Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development.

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“…We would like to note that, during the review process of this article, several other groups' reports describing the same gene under the name "Themis" were published (33)(34)(35)40).…”

Section: Discussionmentioning

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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Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection

Cited by 114 publications

References 46 publications

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

Targeted Sos1 deletion reveals its critical role in early T-cell development

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

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