ArticleThe Journal of biological chemistry2011
Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK).
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 196 papers, 3 of them syntheses that pooled it.
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Who cites it
196 citing papers in PubMed, 3 syntheses or guidelines pooled it, 283 citations in OpenAlex.
- Macrophage-associated kinase signaling in atherosclerosis - a systematic review.Cell communication and signaling : CCS · 2026Pooled it
- Efferocytosis and inflammation: a bibliometric and systematic analysis.Frontiers in medicine · 2025Pooled it
- The Multifaceted Roles of TAM Receptors during Viral Infection.Virologica Sinica · 2021Pooled it
- Article
- TLR4 signaling cascades leading to increases in albumin permeability, nephrin ectodomain shedding, and apoptosis in MPC-5 podocytes.Physiological reports · 2026Article
- Mitochondrial Redox Failure Links Senescence-like Foam Cell Stress to Ferroptosis and Plaque Non-Resolution in Atherosclerosis.Antioxidants (Basel, Switzerland) · 2026Review
- Targeting Inflammation in Atherosclerotic Cardiovascular Disease: Mechanisms and Emerging Therapies.Immunological reviews · 2026Review
- Age-dependent induction of ER stress in retinal pigment epithelium impairs phagocytosis via ADAM17-dependent MERTK shedding.The Journal of biological chemistry · 2026Article
- The ErbB-tyrosine kinase inhibitor, neratinib, has anti-inflammatory effects in multimorbidity by increasing macrophage efferocytosis via the upregulation of MerTK.Journal of inflammation (London, England) · 2026Article
- Suppression of cardiac allograft vasculopathy by a macrophage efferocytosis receptor.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2026Article
- Macrophage efferocytosis in cardiovascular disease: mechanisms and therapeutic implications.ImmunoHorizons · 2026Review
- More Than a Cleanup Crew: The Expanding Biology of Efferocytosis.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Macrophages Are Critical Inducers of Bleomycin-Induced Fibrosis in a Systemic Scleroderma Model.The American journal of pathology · 2026Article
- Peripheral nerve injury reduces macrophage efferocytosis to facilitate neuropathic pain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- NLRP3/Caspase-1 Regulate Macrophage Efferocytosis by Modulating ADAM17-Mediated MerTK Cleavage in Liver Ischemia-Reperfusion Injury.Research (Washington, D.C.) · 2026Article
- Efferocytosis failure in chronic rhinosinusitis with nasal polyps: receptor-level mechanisms of unresolved type 2 inflammation.Frontiers in immunology · 2026Review
- ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis.Frontiers in pharmacology · 2026Review
- Efferocytosis: The Silent Guardian of Tissue Homeostasis and Cardiovascular Health.Journal of cardiovascular development and disease · 2025Review
- Vitamin B12-Loaded Chitosan Nanoparticles Promote Skeletal Muscle Injury Repair in Aged Rats via Amelioration of Aging-Suppressed Efferocytosis.Biomolecules · 2025Article
- Macrophage DNases Limit Neutrophil Extracellular Trap-Mediated Defective Efferocytosis in Atherosclerosis.Circulation research · 2025Article
136 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Mer tyrosine kinase (MerTK) is an integral membrane protein that is preferentially expressed by phagocytic cells, where it promotes efferocytosis and inhibits inflammatory signaling. Proteolytic cleavage of MerTK at an unidentified site leads to shedding of its soluble ectodomain (soluble MER; sMER), which can inhibit thrombosis in mice and efferocytosis in vitro. Herein, we show that MerTK is cleaved at proline 485 in murine macrophages. Site-directed deletion of 6 amino acids spanning proline 485 rendered MerTK resistant to proteolysis and suppression of efferocytosis by cleavage-inducing stimuli. LPS is a known inducer of MerTK cleavage, and the intracellular signaling pathways required for this action are unknown. LPS/TLR4-mediated generation of sMER required disintegrin and metalloproteinase ADAM17 and was independent of Myd88, instead requiring TRIF adaptor signaling. LPS-induced cleavage was suppressed by deficiency of NADPH oxidase 2 (Nox2) and PKCδ. The addition of the antioxidant N-acetyl cysteine inhibited PKCδ, and silencing of PKCδ inhibited MAPK p38, which was also required. In a mouse model of endotoxemia, we discovered that LPS induced plasma sMER, and this was suppressed by Adam17 deficiency. Thus, a TRIF-mediated pattern recognition receptor signaling cascade requires NADPH oxidase to activate PKCδ and then p38, culminating in ADAM17-mediated proteolysis of MerTK. These findings link innate pattern recognition receptor signaling to proteolytic inactivation of MerTK and generation of sMER and uncover targets to test how MerTK cleavage affects efferocytosis efficiency and inflammation resolution in vivo.
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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.