ArticleMolecular biology of the cell2014
The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis.
Article in Molecular biology of the cell, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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80 citing papers in PubMed, 121 citations in OpenAlex.
- Spatio-temporal mechanosensitive phagocytic response of retinal pigment epithelial cells to reversible changes in substrate stiffness.Acta biomaterialia · 2026Article
- Hit the bull's eye: Engineered extracellular vesicles for targeted therapy.Bioactive materials · 2026Review
- Restricting efferocytosis pathway to CD91 via phosphatidylserine-targeting chimeric protein augments antitumor immune responses.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Aging Impairs Macrophage Phagocytosis Through Mitochondrial ROS-Induced Collagen Production.Aging cell · 2026Article
- Peripheral immunochemical considerations in Parkinson disease: sources, targets and crosstalk mechanisms.Journal of translational medicine · 2026Review
- Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.Nature immunology · 2026Article
- MERTK coordinates efferocytosis by regulating integrin localization and activation.Journal of cell science · 2026Article
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- Efferocytosis in tissue engineering: A comprehensive review of emerging therapeutic strategies for enhanced tissue repair and regeneration.Bioactive materials · 2025Review
- Impaired Efferocytosis of Pericytes and Vascular Smooth Muscle Cells in Diabetic Retinopathy.Cells · 2025Review
- Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease.Signal transduction and targeted therapy · 2025Review
- Targeting Frequent Efferocytosis in Tumor Microenvironment is a New Direction for Cancer Treatment.Small science · 2025Review
- Phytochemical-mediated efferocytosis and autophagy in inflammation control.Cell death discovery · 2024Review
- Extraction of redox extracellular vesicles using exclusion-based sample preparation.Analytical and bioanalytical chemistry · 2024Article
- Directed protein engineering identifies a human TIM-4 blocking antibody that enhances anti-tumor response to checkpoint inhibition in murine colon carcinoma.Antibody therapeutics · 2024Article
- Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.Nature metabolism · 2024Article
- Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.Journal of neurovirology · 2024Article
- All-trans retinoic acid and dexamethasone regulate phagocytosis-related gene expression and enhance dead cell uptake in C2C12 myoblast cells.Scientific reports · 2023Article
- Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.bioRxiv : the preprint server for biology · 2023Article
20 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
T-cell immunoglobulin mucin protein 4 (TIM4), a phosphatidylserine (PtdSer)-binding receptor, mediates the phagocytosis of apoptotic cells. How TIM4 exerts its function is unclear, and conflicting data have emerged. To define the mode of action of TIM4, we used two distinct but complementary approaches: 1) we compared bone marrow-derived macrophages from wild-type and TIM4(-/-) mice, and 2) we heterologously expressed TIM4 in epithelioid AD293 cells, which rendered them competent for engulfment of PtdSer-bearing targets. Using these systems, we demonstrate that rather than serving merely as a tether, as proposed earlier by others, TIM4 is an active participant in the phagocytic process. Furthermore, we find that TIM4 operates independently of lactadherin, which had been proposed to act as a bridging molecule. Of interest, TIM4-driven phagocytosis depends on the activation of integrins and involves stimulation of Src-family kinases and focal adhesion kinase, as well as the localized accumulation of phosphatidylinositol 3,4,5-trisphosphate. These mediators promote recruitment of the nucleotide-exchange factor Vav3, which in turn activates small Rho-family GTPases. Gene silencing or ablation experiments demonstrated that RhoA, Rac1, and Rac2 act synergistically to drive the remodeling of actin that underlies phagocytosis. Single-particle detection experiments demonstrated that TIM4 and β1 integrins associate upon receptor clustering. These findings support a model in which TIM4 engages integrins as coreceptors to evoke the signal transduction needed to internalize PtdSer-bearing targets such as apoptotic cells.
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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.