ArticleThe Journal of experimental medicine2023
GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1.
Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed, 10 citations in OpenAlex.
- Structural and mechanistic insights into the constitutive Themis-Grb2 complex in T cell signalling.Nature communications · 2026Article
- The double-positive cells in the tumor microenvironment.Journal of translational internal medicine · 2026Article
- ZDHHC21-driven S-palmitoylation of Themis regulates the function of T cells and maintains homeostatic balance.Cell communication and signaling : CCS · 2025Article
- Identification of Grb2 protein as a potential mediator of macrophage activation in acute pancreatitis based on bioinformatics and experimental verification.Frontiers in immunology · 2025Article
- The partitioning of TCR repertoires by thymic selection.The Journal of experimental medicine · 2024Review
- THEMIS promotes T cell development and maintenance by rising the signaling threshold of the inhibitory receptor BTLA.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Positive regulation of Vav1 by Themis controls CD4 T cell pathogenicity in a mouse model of central nervous system inflammation.Cellular and molecular life sciences : CMLS · 2024Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS-GRB2-SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis-/- thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4+CD8+ thymocytes to low affinity positively selecting self-ligands.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.