ArticleScience signaling2013
A physical interaction between the adaptor proteins DOK3 and DAP12 is required to inhibit lipopolysaccharide signaling in macrophages.
Article in Science signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease.Scientific reports · 2015Pooled it
- TREM2 in neurodegenerative diseases and acute neurological injuries: mechanisms to targeted therapies.Cell communication and signaling : CCS · 2026Review
- The role of DAP12 in immune-related inflammatory diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- Soluble Triggering Receptor Expressed on Myeloid Cells 2 is a Biomarker but Not a Mediator of Fibrosing Steatohepatitis.Gastro hep advances · 2026Article
- The Role of TREM2 After Stroke: From Mechanisms to Therapeutic Potential.Molecular neurobiology · 2025Review
- Magnolol Ameliorates Depression Through Modulating the TREM2-DOK3-ERK Pathway.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look.Frontiers in immunology · 2024Review
- Function and mechanism of TREM2 in bacterial infection.PLoS pathogens · 2024Review
- The biology of TREM receptors.Nature reviews. Immunology · 2023Review
- Article
- Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.Nature immunology · 2023Article
- The Role of ERK1/2 Pathway in the Pathophysiology of Alzheimer's Disease: An Overview and Update on New Developments.Cellular and molecular neurobiology · 2023Review
- TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.Molecular neurodegeneration · 2022Review
- Dysregulation of Human Somatic piRNA Expression in Parkinson's Disease Subtypes and Stages.International journal of molecular sciences · 2022Article
- Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration.Frontiers in cellular neuroscience · 2022Review
- DOK3 maintains intestinal homeostasis by suppressing JAK2/STAT3 signaling and S100a8/9 production in neutrophils.Cell death & disease · 2021Article
- Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma.BMC cancer · 2021Article
- Article
- DOK3 is involved in microglial cell activation in neuropathic pain by interacting with GPR84.Aging · 2020Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
DNAX-activating protein of 12 kD (DAP12) is an immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein found in myeloid cells and natural killer cells, and it couples to various receptors that mediate either cellular activation or inhibition. DAP12 inhibits Toll-like receptor (TLR) signaling, such as that of TLR4 in response to its ligand lipopolysaccharide (LPS), as well as cytokine responses by coupling to TREM2 (triggering receptor expressed on myeloid cells 2) at the plasma membrane. Understanding the mechanisms that inhibit inflammatory responses in macrophages is important for the development of therapies to treat inflammatory diseases. We show that inhibition of LPS responses by DAP12 is mediated by the adaptor protein DOK3 (downstream of kinase 3). DOK3 physically associated with the ITAM of DAP12 through its phosphotyrosine-binding domain. In response to LPS, DOK3 was phosphorylated in a DAP12- and Src-dependent manner, which led to translocation of phosphorylated DOK3 to the plasma membrane. DOK3-deficient cells exhibited increased production of proinflammatory cytokines and activation of extracellular signal-regulated kinase (ERK). Compared to wild-type mice, DOK3-deficient mice had increased susceptibility to challenge with a sublethal dose of LPS and produced increased serum concentrations of the inflammatory cytokine tumor necrosis factor-α (TNF-α). Together, these data suggest the mechanism by which DAP12 and TREM2 inhibit LPS signaling in macrophages to prevent inflammation.
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