ArticleeLife2021
Molecular features underlying differential SHP1/SHP2 binding of immune checkpoint receptors.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
50 citing papers in PubMed, 51 citations in OpenAlex.
- Beyond Hemostasis: Platelets' Multifaceted Functions in Immune Responses.Life (Basel, Switzerland) · 2026Review
- AncestralAnimals : an open access journal from MDPI · 2026Article
- Targeting the pMHC-TCR Interaction: Molecular Strategies and Therapeutic Potential in Autoimmunity.International journal of molecular sciences · 2026Review
- PD1-induced Shp2 condensation organizes inhibitory signalosomes through selective substrate partitioning.bioRxiv : the preprint server for biology · 2026Article
- Cancer-Causing Mutations Alter the Interplay Between Loop Dynamics and Catalysis in the Protein Tyrosine Phosphatases SHP-1 and SHP-2.bioRxiv : the preprint server for biology · 2026Article
- Screening of tyrosine phosphatase SHP2 (PTPN11) inhibitors from natural products with therapeutic potential for receptor tyrosine kinase-driven cancer.Journal of pharmaceutical analysis · 2026Article
- PD-1 suppresses CAR signaling by forming the inhibitory signalosome colocalizing to CAR microclusters.Communications biology · 2026Article
- Bacterial EPIYA/EPIYA-like effector motifs and host regulatory pY-SH2 logic: a sequence-informed three-layer convergence model.Frontiers in cellular and infection microbiology · 2026Article
- The BTLA/HVEM axis as a key regulator for stratified functional cure in chronic hepatitis B.Frontiers in immunology · 2026Review
- Inhibitory immune checkpoints in preeclampsia: current landscape, mechanisms, and clinical perspectives.Frontiers in immunology · 2026Review
- The Expanding Role of ILC2s in Allergic Airways Disease.Allergy · 2026Review
- PTPN6/SHP-1 in autoimmune disease: immune tolerance, regulatory mechanisms, and therapeutic targeting.Frontiers in immunology · 2026Review
- BTLA: An Emerging Immune Checkpoint Target in Cancer Immunotherapy.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Review
- T lymphocyte-specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Tumour Glyco-Code: Sialylation as a Mediator of Stromal Cell Immunosuppression in the Tumour Microenvironment.European journal of immunology · 2025Review
- Development of a Peptide Inhibitor Targeting the C-SH2 Domain of the SHP2 Phosphatase.Chembiochem : a European journal of chemical biology · 2025Article
- TIM-3 teams up with PD-1 in cancer immunotherapy: mechanisms and perspectives.Molecular biomedicine · 2025Review
- Dys-regulated phosphatidylserine externalization as a cell intrinsic immune escape mechanism in cancer.Cell communication and signaling : CCS · 2025Review
- Genotype-driven sensitivity of mice to tick-borne encephalitis virus correlates with differential host responses in peripheral macrophages and brain.Journal of neuroinflammation · 2025Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
A large number of inhibitory receptors recruit SHP1 and/or SHP2, tandem-SH2-containing phosphatases through phosphotyrosine-based motifs immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). Despite the similarity, these receptors exhibit differential effector binding specificities, as exemplified by the immune checkpoint receptors PD-1 and BTLA, which preferentially recruit SHP2 and SHP1, respectively. The molecular basis by which structurally similar receptors discriminate SHP1 and SHP2 is unclear. Here, we provide evidence that human PD-1 and BTLA optimally bind to SHP1 and SHP2 via a bivalent, parallel mode that involves both SH2 domains of SHP1 or SHP2. PD-1 mainly uses its ITSM to prefer SHP2 over SHP1 via their C-terminal SH2 domains (cSH2): swapping SHP1-cSH2 with SHP2-cSH2 enabled PD-1:SHP1 association in T cells. In contrast, BTLA primarily utilizes its ITIM to prefer SHP1 over SHP2 via their N-terminal SH2 domains (nSH2). The ITIM of PD-1, however, appeared to be de-emphasized due to a glycine at pY+1 position. Substitution of this glycine with alanine, a residue conserved in BTLA and several SHP1-recruiting receptors, was sufficient to induce PD-1:SHP1 interaction in T cells. Finally, structural simulation and mutagenesis screening showed that SHP1 recruitment activity exhibits a bell-shaped dependence on the molecular volume of the pY+1 residue of ITIM. Collectively, we provide a molecular interpretation of the SHP1/SHP2-binding specificities of PD-1 and BTLA, with implications for the mechanisms of a large family of therapeutically relevant receptors.
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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.