ArticleBiochemical pharmacology2018
Src family kinase tyrosine phosphorylates Toll-like receptor 4 to dissociate MyD88 and Mal/Tirap, suppressing LPS-induced inflammatory responses.
Article in Biochemical pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 41 citations in OpenAlex.
- Lentinan Attenuates Experimental Atherosclerosis by Regulating Macrophage HCK/GUSB Expression and Amino Acid Metabolic Remodeling.Cardiovascular drugs and therapy · 2026Article
- Zfand5 terminates TLR3/4 signaling and necroptosis by targeting TRIF to the proteasome for degradation.Cell death & disease · 2026Article
- Artemisinin attenuates 3-nitropropionic acid-induced neurodegeneration via HMGB1/TLR4/NF-κB modulation in a rat model of huntington's disease.Archives of pharmacal research · 2026Article
- Integrative network pharmacology and experimental validation of anti-inflammatory triterpenoids from hawthorn leaves.Scientific reports · 2025Article
- Anti-Tumor Activity and Mechanism of Silibinin Based on Network Pharmacology and Experimental Verification.Molecules (Basel, Switzerland) · 2024Article
- ADAM10-a "multitasker" in sepsis: focus on its posttranslational target.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2023Review
- The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine.Frontiers in pharmacology · 2023Review
- Sorafenib inhibits LPS-induced inflammation by regulating Lyn-MAPK-NF-kB/AP-1 pathway and TLR4 expression.Cell death discovery · 2022Article
- The transmembrane adapter SCIMP recruits tyrosine kinase Syk to phosphorylate Toll-like receptors to mediate selective inflammatory outputs.The Journal of biological chemistry · 2022Article
- Chronic Intestinal Inflammation Suppresses Brain Activity by Inducing Neuroinflammation in Mice.The American journal of pathology · 2022Article
- Overexpression of Toll-like receptor 4 contributes to the internalization and elimination of Escherichia coli in sheep by enhancing caveolae-dependent endocytosis.Journal of animal science and biotechnology · 2021Article
- Src-family Protein Tyrosine Kinases: A promising target for treating Cardiovascular Diseases.International journal of medical sciences · 2021Review
- Screening of key genes related to the prognosis of mouse sepsis.Bioscience reports · 2020Article
- Autotaxin loss accelerates intestinal inflammation by suppressing TLR4-mediated immune responses.EMBO reports · 2020Article
- Protein-N-myristoylation-dependent phosphorylation of serine 13 of tyrosine kinase Lyn by casein kinase 1γ at the Golgi during intracellular protein traffic.Scientific reports · 2020Article
- Integrated Gene Expression Profiling Analysis Reveals Probable Molecular Mechanism and Candidate Biomarker in Anti-TNFα Non-Response IBD Patients.Journal of inflammation research · 2020Article
- Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling.Journal of neuroinflammation · 2019Article
- Anti-Inflammatory Effects ofEvidence-based complementary and alternative medicine : eCAM · 2019Article
- The Caspase Inhibitor Z-VAD-FMK Alleviates Endotoxic Shock via Inducing Macrophages Necroptosis and Promoting MDSCs-Mediated Inhibition of Macrophages Activation.Frontiers in immunology · 2019Article
- Identification of Compounds That Prolong Type I Interferon Signaling as Potential Vaccine Adjuvants.SLAS discovery : advancing life sciences R & D · 2018Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Src family kinases (SFKs) are a family of protein tyrosine kinases containing nine members: Src, Lyn, Fgr, Hck, Lck, Fyn, Blk, Yes, and Ylk. Although SFK activation is a major immediate signaling event in LPS/Toll-like receptor 4 (TLR4) signaling, its precise role has remained elusive due to various contradictory results obtained from a certain SFK member-deficient mice or cells. The observed inconsistencies may be due to the compensation or redundancy by other SFKs upon a SFK deficiency. The chemical rescuing approach was suggested to induce temporal and precise SFK activation in living cells, thereby limiting the chance of cellular adaption to a SFK-deficient condition. Using the rescuing approach, we demonstrate that restoring SFK activity not only induces tyrosine phosphorylation of TLR4, but also inhibits LPS-induced NFκB and JNK1/2 activation and consequently suppresses LPS-induced cytokine production. TLR4 normally recruits TIR domain-containing adaptors in response to LPS, however, temporally restored SFK activation disrupts the LPS-induced association of MyD88 and Mal/Tirap with TLR4. Additionally, using kinase-dead SFK-Lyn (Y397/508F) and constitutively active SFK-Lyn (Y508F), we found that the kinase-dead SFK inhibits TLR4 tyrosine phosphorylation with reduced binding affinity to TLR4, while the kinase-active SFK strongly binds to TLR4 and promotes TLR4 tyrosine phosphorylation, suggesting that SFK kinase activity is required for TLR4 tyrosine phosphorylation and TLR4-SFK interaction. Together, our results demonstrate that SFK activation induces TLR4 tyrosine phosphorylation, consequently dissociating MyD88 and Mal/Tirap from TLR4 and inhibiting LPS-induced inflammatory responses, suggesting a negative feedback loop regulated by SFK-induced tyrosine phosphorylation in TLR4.
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