ArticleEuropean journal of immunology2020
TAM receptors attenuate murine NK-cell responses via E3 ubiquitin ligase Cbl-b.
Article in European journal of immunology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 33 citations in OpenAlex.
- Osimertinib Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Mechanisms and Therapeutic Strategies.MedComm · 2026Review
- Targeting macrophage-driven NK cell immunosuppression to improve cancer immunotherapy.Journal for immunotherapy of cancer · 2026Review
- Navigating TAM receptor dynamics in tumour immunotherapy.Cancer immunology, immunotherapy : CII · 2025Review
- AXL: shapers of tumor progression and immunosuppressive microenvironments.Molecular cancer · 2025Review
- Enhancing natural killer cell anti-tumour activity through macrophage manipulation.Frontiers in immunology · 2025Review
- Mechanisms of Cbl-Mediated Ubiquitination of Proteins in T and Natural Killer Cells and Effects on Immune Cell Functions.Life (Basel, Switzerland) · 2024Review
- MERTK inhibition selectively activates a DC - T-cell axis to provide anti-leukemia immunity.Leukemia · 2024Article
- Inhibition of Cbl-b restores effector functions of human intratumoral NK cells.Journal for immunotherapy of cancer · 2024Article
- Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization.Signal transduction and targeted therapy · 2024Review
- CD73 promotes non-small cell lung cancer metastasis by regulating Axl signaling independent of GAS6.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- GAS6/TAM Axis as Therapeutic Target in Liver Diseases.Seminars in liver disease · 2024Article
- NK cell-based tumor immunotherapy.Bioactive materials · 2024Review
- CRISPR-Cas9-Based Gene Knockout of Immune Checkpoints in Expanded NK Cells.International journal of molecular sciences · 2023Article
- Tumour-associated macrophages as a potential target to improve natural killer cell-based immunotherapies.Essays in biochemistry · 2023Article
- Chicken-derived MERTK protein inhibits Newcastle disease virus replication by increasing STAT1 phosphorylation in DF-1 cells.Virus research · 2023Article
- Structure and functions of Mer, an innate immune checkpoint.Frontiers in immunology · 2023Review
- The expanding role for small molecules in immuno-oncology.Nature reviews. Drug discovery · 2022Review
- GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells.Frontiers in immunology · 2022Article
- E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.Clinical and experimental immunology · 2021Review
- Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
TAM receptors (Tyro3, Axl, and Mer) are receptor tyrosine kinases (RTKs) that are expressed by multiple immune cells including NK cells. Although RTKs typically enhance cellular functions, TAM receptor ligation blocks NK-cell activation. The mechanisms by which RTKs block NK-cell signaling downstream of activating receptors are unknown. In this report, we demonstrate that TAM receptors attenuate NK cell responses via the activity of E3 ubiquitin ligase Casitas B lineage lymphoma b (Cbl-b). Specifically, we show that Tyro3, Axl, and Mer phosphorylate Cbl-b, and Tyro3 ligation activates Cbl-b by phosphorylating tyrosine residues 133 and 363. Ligation of TAM receptors by their ligand Gas6 suppresses activating receptor-stimulated NK-cell functions such as IFN-γ production and degranulation, in a TAM receptor kinase- and Cbl-b-dependent manner. Moreover, Gas6 ligation induces the degradation of LAT1, a transmembrane adaptor protein required for NK cell activating receptor signaling, in WT but not in Cbl-b knock-out NK cells. Together, these results suggest that TAM receptors may attenuate NK-cell function by phosphorylating Cbl-b, which in turn dampens NK-cell activation signaling by promoting the degradation of LAT1. Our data therefore support a mechanism by which RTKs attenuate, rather than stimulate, signaling pathways via the activation of ubiquitin ligases.
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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.