Affinage

TICAM2

TIR domain-containing adapter molecule 2 · UniProt Q86XR7

Length
235 aa
Mass
26.9 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TICAM2 (TRAM) is a TIR domain-containing sorting adaptor that bridges innate immune receptors to downstream signaling cascades at endosomal membranes, functioning as the specificity determinant for the MyD88-independent arm of TLR4 signaling and extending to TLR2 and IL-18 receptor pathways. N-terminally myristoylated TRAM resides at the Rab11A-positive endocytic recycling compartment and, upon LPS stimulation, is delivered to early endosomes where it physically bridges TLR4 to TRIF/TICAM-1 through TIR-domain interactions (key residues E87/D88/D89), activating IRF3-dependent type I interferon production; it also engages TRAF6 via E183 to support inflammatory cytokine output (PMID:14519765, PMID:14556004, PMID:28630139, PMID:24812060). TRAM activity is positively regulated by tyrosine phosphorylation and negatively regulated by the phosphatase PTPN4 and by the inhibitory splice variant TAG, which displaces TRIF from late endosomes (PMID:25825441, PMID:19412184). Beyond canonical TLR4 signaling, TRAM serves as a sorting adaptor directing MyD88 to endosomes in TLR2 and IL-18 pathways, promotes phagocytosis through a FIP2–Rac1/Cdc42 axis, and drives neutrophil and monocyte inflammatory polarization via c-SRC/STAT1 activation (PMID:25385819, PMID:22685567, PMID:30883606, PMID:32873853).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Identification of TRAM as the adaptor that physically bridges TLR4 to TRIF resolved how the MyD88-independent arm of LPS signaling is specifically initiated — TRAM-deficient mice completely lost TLR4-mediated IFN-β induction while other TLR responses remained intact.

    Evidence Co-IP, dominant-negative constructs, reporter assays in cell lines (multiple labs); gene-targeted knockout mice with cytokine measurements

    PMID:14517278 PMID:14519765 PMID:14556004

    Open questions at the time
    • Subcellular site of TRAM-TLR4 interaction was unknown
    • No structural information on the TRAM TIR domain or its interfaces
    • Whether TRAM functions beyond TLR4 was not addressed
  2. 2006 Medium

    The finding that vascular endothelial cells express negligible TRAM — restricting them to MyD88-only TLR4 signaling unless TRAM is reconstituted — established that TRAM expression level is a gate-keeping determinant of pathway availability across cell types.

    Evidence TRAM overexpression in primary endothelial cells, MyD88-deficient mice, NF-κB and CXCL10 reporter assays

    PMID:16574902

    Open questions at the time
    • Transcriptional or epigenetic regulation of TRAM expression was not defined
    • Generalizability to other TRAM-low cell types untested
  3. 2008 High

    Demonstrating that TLR4 first signals via TIRAP-MyD88 at the plasma membrane and then, upon endocytosis, activates TRAM-TRIF from early endosomes resolved the spatiotemporal logic of dual TLR4 signaling pathways.

    Evidence Live-cell imaging, subcellular fractionation, endocytosis inhibitors, genetic epistasis with adaptor-deficient cells; confocal co-localization and co-IP

    PMID:18222170 PMID:18297073

    Open questions at the time
    • Machinery delivering TRAM to the endosome was undefined
    • Whether TRAM-TRIF signaling is restricted to early versus late endosomes was unclear
  4. 2009 High

    Discovery of TAG, an inhibitory splice variant containing a GOLD domain fused to TRAM's TIR, revealed a built-in negative feedback mechanism that displaces TRIF from TRAM on late endosomes to attenuate IRF3 signaling.

    Evidence Confocal microscopy (Rab7a co-localization), siRNA, co-IP, luciferase reporters

    PMID:19412184

    Open questions at the time
    • Regulation of TAG splicing was not determined
    • Stoichiometry of TAG versus TRAM at endosomes unknown
  5. 2012 High

    Extending TRAM function beyond TLR4, the finding that TRAM directly binds MyD88's TIR domain and is required for IL-18 signal transduction revealed TRAM as a more general sorting adaptor for MyD88-dependent pathways.

    Evidence In vitro binding, NMR mapping, TRAM-deficient mice, live-cell imaging

    PMID:22685567

    Open questions at the time
    • Whether TRAM sorts MyD88 in other IL-1 family receptor pathways was not tested
    • Structural basis of TRAM-MyD88 versus TRAM-TRIF selectivity unresolved
  6. 2013 Medium

    Two studies defined trafficking machinery and functional TIR-domain interfaces: Arf6 was shown to transport TRAM to the ERC and mediate LPS internalization for IRF3 activation, while decoy peptides from TRAM's BB loop and C helix specifically disrupted TRAM-TLR4 interaction and LPS-induced cytokines in vivo.

    Evidence Arf6 inhibition with KO macrophages and localization imaging; cell-permeating decoy peptides with co-IP and in vivo LPS challenge

    PMID:23345333 PMID:24297182

    Open questions at the time
    • Identity of the kinase that phosphorylates TRAM was unknown
    • How Arf6 and Rab11A cooperate in TRAM trafficking was not resolved
  7. 2014 High

    TRAM was established as a sorting adaptor for TLR2 endosomal signaling (IRF7/IRF3 activation and CCL5 induction) and shown to interact directly with TRAF6 via E183, a site whose mutation ablates inflammatory cytokine production — broadening TRAM's receptor scope and defining a second effector interaction beyond TRIF.

    Evidence KO macrophages, reciprocal co-IP, domain mutagenesis, confocal co-localization, cytokine assays, reconstitution

    PMID:24812060 PMID:25385819 PMID:25505250

    Open questions at the time
    • Whether TRAM engages TLR2 and TLR4 through the same TIR interface was not resolved
    • Relative contributions of TRAF6 versus TRIF downstream of TRAM were not quantified
  8. 2015 High

    TRAM tyrosine phosphorylation was identified as an activating modification required for TRIF engagement and IRF3 activation, with PTPN4 serving as the negative regulator (phosphatase) that reverses this modification; simultaneously, TIRF/FRAP imaging established that TRAM traffics via Rab11A from the ERC independently of CD14/LPS.

    Evidence Phosphorylation assays, PTPN4 overexpression/knockdown, co-IP, IRF3 reporters; TIRF microscopy, FRAP, Rab11A co-localization

    PMID:25707286 PMID:25825441 PMID:26527544

    Open questions at the time
    • Identity of the tyrosine kinase that phosphorylates TRAM was not determined
    • Specific phosphorylation sites on TRAM were not mapped
  9. 2017 High

    NMR structural analysis of the TRAM TIR domain defined the molecular mechanism: TRAM dimerizes beneath TLR4's TIR dimer on the endosomal membrane (anchored by N-terminal myristoylation), creating a composite surface for TRIF recruitment through the E87/D88/D89 motif, with D91/E92 cooperatively determining endosomal localization.

    Evidence NMR structural analysis, site-directed mutagenesis, subcellular localization assays

    PMID:28630139

    Open questions at the time
    • No high-resolution full-length TRAM structure or TRAM-TLR4-TRIF ternary complex structure available
    • Stoichiometry of the signaling complex in native membranes not determined
  10. 2018 High

    SLAMF1 was identified as a receptor that controls Rab11-dependent delivery of TRAM from the ERC to E. coli phagosomes, with direct SLAMF1-TRAM binding (residues 68–95 of TRAM) required for IFN-β induction and bacterial killing, connecting pathogen recognition to TRAM trafficking.

    Evidence Endogenous co-IP, domain mapping, live-cell imaging, SLAMF1 knockdown, subcellular fractionation

    PMID:29440514

    Open questions at the time
    • Whether SLAMF1-TRAM axis operates with non-bacterial TLR4 ligands was not tested
    • Structural basis of SLAMF1-TRAM interaction not resolved
  11. 2019 High

    TRAM was shown to promote phagocytosis through a FIP2–Rac1/Cdc42 axis, directly linking TLR4 sorting adaptor function to actin remodeling at phagocytic cups — a signaling-independent role in innate effector function.

    Evidence Co-IP, TRAM-deficient THP-1 cells, confocal imaging, GTPase activation assays, phagocytosis assays

    PMID:30883606

    Open questions at the time
    • Whether TRAM's phagocytic role requires its TIR domain or myristoylation was not dissected
    • Relationship between FIP2-mediated phagocytosis and TRIF-dependent signaling unclear
  12. 2020 Medium

    TRAM was found to drive neutrophil exhaustion through c-SRC/STAT1 signaling upon prolonged LPS exposure, expanding its role from acute signaling adaptor to a mediator of sustained inflammatory programming in myeloid cells.

    Evidence TICAM2-deficient mice, primary neutrophil cultures, SFK inhibitor (Dasatinib), flow cytometry, in vivo mucosal damage model

    PMID:32873853

    Open questions at the time
    • Direct physical link between TRAM and c-SRC not established
    • Whether TRIF is required for this SRC/STAT1 axis was not tested
    • Single lab finding without independent replication
  13. 2021 Medium

    TRAM was shown to control monocyte inflammatory polarization via c-SRC activation of STAT1/STAT5 and suppression of PPARγ-regulated CD200R, with TRAM deficiency promoting a resolving phenotype protective against atherosclerosis — placing TRAM at the intersection of innate signaling and metabolic reprogramming.

    Evidence TRAM-deficient mice on high-fat diet, adoptive transfer, kinase pathway analysis

    PMID:34499622

    Open questions at the time
    • Direct biochemical mechanism linking TRAM to c-SRC activation not defined
    • Whether TAG splice variant modulates monocyte polarization not addressed
    • Single lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the kinase(s) that phosphorylate TRAM's tyrosine residues, the structural basis of the full TRAM-TLR4-TRIF ternary signaling complex, how TRAM discriminates between TRIF-dependent and MyD88-dependent downstream signaling at different receptors, and whether TRAM's phagocytic and SRC-dependent polarization functions are independent of its classical role as a TRIF sorting adaptor.
  • No kinase identified for TRAM tyrosine phosphorylation
  • No high-resolution ternary complex structure
  • Mechanistic basis of TRAM selectivity between TRIF and MyD88 pathways at different receptors unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0005198 structural molecule activity 1
Localization
GO:0005768 endosome 6 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-168256 Immune System 8 R-HSA-162582 Signal Transduction 6
Partners
MYD88PTPN4RAB11FIP2SLAMF1TICAM1TLR2TLR4TRAF6
Complex memberships
TLR4-TRAM-TRIF signalosome

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 TICAM-2/TRAM physically bridges TLR4 and TICAM-1/TRIF: it binds directly to TLR4's cytoplasmic domain and to TICAM-1, thereby transmitting LPS-TLR4 signaling to TICAM-1 which activates IRF-3 and IFN-β production, while exhibiting minimal intrinsic ability to activate NF-κB or the IFN-β promoter itself. Co-immunoprecipitation, overexpression/dominant-negative constructs, reporter assays in cell lines The Journal of Biological Chemistry High 14519765
2003 TRAM activates IRF-3, IRF-7, and NF-κB-dependent signaling pathways downstream of TLR4 (but not TLR3); TRAM interacts with TRIF, Mal/TIRAP, and TLR4 but not TLR3, placing it specifically in the MyD88-independent LPS-TLR4 pathway. Dominant-negative constructs, siRNA knockdown, co-immunoprecipitation, reporter assays The Journal of Experimental Medicine High 14517278
2003 TRAM-deficient mice specifically lack TLR4-mediated MyD88-independent IFN-β production and downstream signaling cascades, while responses to other TLR ligands remain intact, establishing TRAM as the specificity factor for the MyD88-independent component of TLR4 signaling. Gene targeting (knockout mice), cytokine measurements, signaling cascade analysis Nature Immunology High 14556004
2008 TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed, whereupon TRAM-TRIF signaling is activated from early endosomes; endocytosis of the TLR4 complex is required for TRAM-dependent type I interferon induction. Live-cell imaging, subcellular fractionation, endocytosis inhibitors, genetic epistasis with adaptor-deficient cells Nature Immunology High 18297073
2008 LPS induces upregulation of TLR4 association with TRAM and their subsequent co-translocation into endosome/lysosome; TRAM recruits TRIF to the plasma membrane and the internalized TLR4-TRAM complex colocalizes with TRAF3 in endosomes/lysosomes. Co-immunoprecipitation, confocal microscopy, subcellular fractionation Biochemical and Biophysical Research Communications Medium 18222170
2009 TAG, a splice variant of TRAM containing a GOLD (Golgi dynamics) domain fused to TRAM's TIR domain, localizes to late endosomes (Rab7a-positive) after LPS stimulation and acts as an inhibitor of the MyD88-independent pathway by displacing TRIF from TRAM, reducing IRF3 activation and CCL5 (RANTES) induction. Subcellular localization (confocal microscopy), siRNA knockdown, co-immunoprecipitation, luciferase reporter assays Nature Immunology High 19412184
2014 TRAM acts as a sorting adaptor for TLR2 endosomal signaling as well as TLR4: TRAM is required for TLR2-dependent IRF7 activation at the endosome, facilitates movement of MyD88 to endosomes after TLR2 ligand engagement, and interacts with both TLR2 and MyD88. Co-immunoprecipitation, TRAM-deficient macrophages, confocal microscopy, cytokine/IFN induction assays, pathogen infection models Journal of Immunology High 25385819
2014 TRAM also functions in TLR2 signaling: TRAM and TRIF deficiency impairs TLR2-mediated CCL5 induction; TRAM and TLR2 co-localize in early endosomes, and the pathway involves TBK-1, IRF3, and IRF1 downstream. TRAM/TRIF-deficient macrophages, endocytosis inhibitors, co-localization (confocal), cytokine assays The Journal of Biological Chemistry Medium 25505250
2014 TRAM contains a TRAF6-binding motif; TRAM interacts with TRAF6 (confirmed by immunoprecipitation of endogenous, ectopic, and recombinant proteins), and mutation of Glu183 in TRAM abolishes this interaction and significantly reduces inflammatory TNF-α, IL-6, and RANTES production in macrophages. Co-immunoprecipitation (endogenous and ectopic), mutagenesis (E183A), confocal co-localization, luciferase reporters, reconstitution of TRAM-deficient macrophages Journal of Leukocyte Biology High 24812060
2015 TRAM undergoes tyrosine phosphorylation upon TLR4 activation, and this phosphorylation is required for TLR4-induced IRF3 activation. PTPN4 phosphatase dephosphorylates TRAM, inhibiting its cytoplasmic translocation and TRAM-TRIF interaction, thereby specifically suppressing TRIF-dependent IRF3 activation and IFN-β production. Phosphorylation assays, PTPN4 overexpression/knockdown, co-immunoprecipitation, IRF3 activation assays, IFN-β reporter Journal of Immunology High 25825441
2017 NMR structural analysis shows TRAM interacts with TRIF via an acidic amino acid motif (E87/D88/D89); the TICAM-2 TIR domain couples with the dimer of TLR4 TIR domains beneath the membrane, and TICAM-2 itself forms a dimer creating a binding site for TICAM-1. N-terminal myristoylation anchors TICAM-2 to the endosomal membrane, and residues D91/E92 cooperatively determine endosomal localization required for type I IFN induction. NMR structural analysis, site-directed mutagenesis, subcellular localization assays Biochemical Society Transactions High 28630139
2018 SLAMF1 controls trafficking of TRAM from the endocytic recycling compartment (ERC) to E. coli phagosomes in a Rab11-dependent manner; SLAMF1 physically interacts with TRAM (amino acids 68–95 of TRAM and 15 C-terminal residues of SLAMF1), and this interaction is required for TLR4-TRAM-TRIF-dependent IFN-β induction and killing of Gram-negative bacteria. Co-immunoprecipitation (endogenous), domain mapping, live-cell imaging, SLAMF1 knockdown, subcellular fractionation The Journal of Cell Biology High 29440514
2013 The small GTPase Arf6 is required for the TRAM/TRIF pathway: Arf6 mediates transport of TRAM to the endocytic recycling compartment and internalization of LPS, and inhibition of Arf6 blocks LPS-induced IRF3 activation and IRF3-dependent gene transcription without affecting the MyD88 pathway. Arf6 inhibition, Mal-deficient macrophages, IRF3 activation assays, subcellular localization imaging The Journal of Biological Chemistry Medium 24297182
2015 Annexin A2 (AnxA2) facilitates TLR4 internalization and its translocation to early endosomal membranes, activating TRAM-dependent endosomal signaling and release of anti-inflammatory cytokines; AnxA2 deficiency prolongs TLR4 plasma membrane signaling and increases pro-inflammatory cytokine production. AnxA2 knockout mice, biochemical fractionation, TLR4 internalization assays, cytokine measurement Scientific Reports Medium 26527544
2019 TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited to phagocytic cups of E. coli, promoting activation of actin-regulatory GTPases Rac1 and Cdc42; TRAM is required for phagocytosis of both E. coli and S. aureus in human macrophages, linking TLR4 sorting adaptor function to actin remodeling. Co-immunoprecipitation, TRAM-deficient THP-1 monocytes, confocal microscopy, GTPase activation assays, phagocytosis assays PLoS Pathogens High 30883606
2015 LPS-induced TLR4 clustering in plasma membrane puncta containing CD14/LPS and clathrin precedes endocytosis; TRAM is localized to the endocytic recycling compartment (ERC) via Rab11A and is recruited independently of CD14/LPS to early sorting endosomes, establishing spatially distinct trafficking dynamics for TLR4 and TRAM. TIRF microscopy, FRAP, live-cell imaging, Rab11A co-localization, endocytosis assays Traffic Medium 25707286
2012 TRAM is involved in IL-18 signaling: TRAM directly interacts with MyD88-TIR domain in vitro, co-localizes with MyD88 at membrane regions in live cells, and TRAM-deficient mice show impaired IL-18 signal transduction, defining TRAM as a sorting adaptor for MyD88 in the IL-18 pathway. In vitro binding assay, NMR mapping of binding sites, siRNA knockdown, TRAM-deficient mice, live-cell imaging co-localization PLoS One High 22685567
2013 Cell-permeating decoy peptides derived from the TRAM TIR domain BB loop (TM4) and C helix (TM6) block TRAM-TLR4 co-immunoprecipitation and inhibit LPS-induced MyD88-dependent and TRIF-dependent cytokines specifically (not TLR2, TLR9, or RIG-I-like receptor agonists), validating TRAM TIR domain interfaces as functional interaction surfaces. Decoy peptide inhibition, co-immunoprecipitation, cytokine assays, in vivo LPS challenge Journal of Immunology Medium 23345333
2017 Allelic variation in Ticam2 contributes to differential SARS-CoV pathogenesis in mice: Ticam2-/- mice show increased weight loss and pulmonary hemorrhage after SARS-CoV infection, establishing a critical role for TICAM2 in antiviral defense against SARS-CoV. Quantitative trait locus mapping in F2 cross, Ticam2 knockout mice, viral challenge model G3 (Bethesda) Medium 28592648
2020 TICAM2 mediates neutrophil exhaustion downstream of prolonged LPS stimulation: TICAM2-deficient neutrophils show decreased expression of ICAM1, CD11b, and PD-L1 and reduced aggregation; mechanistically, TICAM2 activates Src family kinases (SFK) and STAT1 to drive the exhaustive phenotype. TICAM2-deficient mice, primary neutrophil cultures, SFK inhibitor (Dasatinib), flow cytometry, in vivo mucosal damage model Scientific Reports Medium 32873853
2021 TRAM controls monocyte inflammatory polarization through activation of Src family kinase c-SRC, which induces STAT1/STAT5-regulated CCR2 and SIRP-α and suppresses PPARγ-regulated CD200R; TRAM deficiency enhances PPARγ and Pex5-mediated peroxisome homeostasis, reducing ROS and promoting a resolving monocyte phenotype protective against atherosclerosis. TRAM-deficient mice, high-fat diet atherosclerosis model, adoptive transfer of TRAM-deficient monocytes, kinase pathway analysis JCI Insight Medium 34499622
2006 Vascular endothelial cells express negligible TRAM, restricting TLR4 signaling exclusively to the MyD88-dependent pathway; overexpression of TRAM cDNA in endothelial cells reconstitutes TRIF-dependent NF-κB activation and CXCL10 promoter activity, directly demonstrating that TRAM expression level determines pathway availability. TRAM overexpression in endothelial cells, MyD88-deficient mice, NF-κB reporter assays, gene expression analysis Circulation Research Medium 16574902

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nature immunology 1031 18297073
2003 LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. The Journal of experimental medicine 929 14517278
2003 TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature immunology 759 14556004
2000 The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development. Proceedings of the National Academy of Sciences of the United States of America 432 10823921
1997 TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. The Journal of biological chemistry 315 9346901
2003 TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta. The Journal of biological chemistry 303 14519765
2008 Broad-host-range expression vectors with tightly regulated promoters and their use to examine the influence of TraR and TraM expression on Ti plasmid quorum sensing. Applied and environmental microbiology 267 18606801
2002 Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase. Molecular and cellular biology 226 11971985
2008 Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochemical and biophysical research communications 200 18222170
1996 Signal sequence-dependent function of the TRAM protein during early phases of protein transport across the endoplasmic reticulum membrane. The Journal of cell biology 157 8698819
2004 Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. The Journal of biological chemistry 145 15623538
2002 TRAM, LAG1 and CLN8: members of a novel family of lipid-sensing domains? Trends in biochemical sciences 136 12151215
2001 Delineation of the clotrimazole/TRAM-34 binding site on the intermediate conductance calcium-activated potassium channel, IKCa1. The Journal of biological chemistry 126 11425865
1993 Site-specific photocross-linking reveals that Sec61p and TRAM contact different regions of a membrane-inserted signal sequence. The Journal of biological chemistry 122 8253810
2019 A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC cancer 121 31881853
2009 TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway. Nature immunology 112 19412184
1995 Activity of the Agrobacterium Ti plasmid conjugal transfer regulator TraR is inhibited by the product of the traM gene. Journal of bacteriology 105 7868612
2011 The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 94 21750563
2013 Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovascular research 91 23417039
2014 TRAM is required for TLR2 endosomal signaling to type I IFN induction. Journal of immunology (Baltimore, Md. : 1950) 90 25385819
2008 Local delivery of the KCa3.1 blocker, TRAM-34, prevents acute angioplasty-induced coronary smooth muscle phenotypic modulation and limits stenosis. Arteriosclerosis, thrombosis, and vascular biology 89 18309114
2014 A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling. The Journal of biological chemistry 87 25505250
2007 Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. Journal of immunology (Baltimore, Md. : 1950) 87 17202370
2003 TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. The Journal of biological chemistry 80 12721283
1997 The cytoplasmic DNA-binding protein TraM binds to the inner membrane protein TraD in vitro. Journal of bacteriology 80 9324263
2000 The antiactivator TraM interferes with the autoinducer-dependent binding of TraR to DNA by interacting with the C-terminal region of the quorum-sensing activator. The Journal of biological chemistry 72 10713083
2015 Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Scientific reports 71 26527544
2015 MiR-27a ameliorates inflammatory damage to the blood-spinal cord barrier after spinal cord ischemia: reperfusion injury in rats by downregulating TICAM-2 of the TLR4 signaling pathway. Journal of neuroinflammation 68 25876455
2009 Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. The Journal of biological chemistry 68 19638630
2008 Structural basis of specific TraD-TraM recognition during F plasmid-mediated bacterial conjugation. Molecular microbiology 68 18717787
2017 Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice. G3 (Bethesda, Md.) 67 28592648
1999 Characterization of an E1A-CBP interaction defines a novel transcriptional adapter motif (TRAM) in CBP/p300. Journal of virology 67 10196247
2006 Use of regenerative human acellular tissue (AlloDerm) to reconstruct the abdominal wall following pedicle TRAM flap breast reconstruction surgery. Plastic and reconstructive surgery 66 16816665
2000 Quorum sensing but not autoinduction of Ti plasmid conjugal transfer requires control by the opine regulon and the antiactivator TraM. Journal of bacteriology 64 10648535
2004 Thirty-eight C-terminal amino acids of the coupling protein TraD of the F-like conjugative resistance plasmid R1 are required and sufficient to confer binding to the substrate selector protein TraM. Journal of bacteriology 60 15466052
1999 Modulating quorum sensing by antiactivation: TraM interacts with TraR to inhibit activation of Ti plasmid conjugal transfer genes. Molecular microbiology 59 10564472
2001 TRAM, a predicted RNA-binding domain, common to tRNA uracil methylation and adenine thiolation enzymes. FEMS microbiology letters 58 11313137
2012 General Sensitization of melanoma cells for TRAIL-induced apoptosis by the potassium channel inhibitor TRAM-34 depends on release of SMAC. PloS one 56 22723988
2011 Acyl chain specificity of ceramide synthases is determined within a region of 150 residues in the Tram-Lag-CLN8 (TLC) domain. The Journal of biological chemistry 55 22144673
1982 Promoter mapping and DNA sequencing of the F plasmid transfer genes traM and traJ. Molecular & general genetics : MGG 55 6298579
2017 Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells. Cell death & disease 53 28151482
2000 Monitoring of free TRAM flaps with microdialysis. Journal of reconstructive microsurgery 53 10706199
2018 SLAMF1 is required for TLR4-mediated TRAM-TRIF-dependent signaling in human macrophages. The Journal of cell biology 52 29440514
2012 The 2.5 Å structure of the enterococcus conjugation protein TraM resembles VirB8 type IV secretion proteins. The Journal of biological chemistry 51 23188825
2005 Mutations in the C-terminal region of TraM provide evidence for in vivo TraM-TraD interactions during F-plasmid conjugation. Journal of bacteriology 50 15995191
1997 The enigma of Y chromosome degeneration: TRAM, a novel retrotransposon is preferentially located on the Neo-Y chromosome of Drosophila miranda. Genetics 50 9071582
1992 The TraM protein of the conjugative plasmid F binds to the origin of transfer of the F and ColE1 plasmids. Molecular microbiology 50 1479887
1996 Regulation of the expression of the traM gene of the F sex factor of Escherichia coli. Molecular microbiology 48 8736534
2007 The Troll in Toll: Mal and Tram as bridges for TLR2 and TLR4 signaling. Journal of leukocyte biology 47 17449723
2004 LPS, dsRNA and the interferon bridge to adaptive immune responses: Trif, Tram, and other TIR adaptor proteins. Journal of endotoxin research 47 15120005
2001 Inhibition of the Agrobacterium tumefaciens TraR quorum-sensing regulator. Interactions with the TraM anti-activator. The Journal of biological chemistry 47 11687576
2016 KCa3.1 (IK) modulates pancreatic cancer cell migration, invasion and proliferation: anomalous effects on TRAM-34. Pflugers Archiv : European journal of physiology 46 27752766
2005 TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of type 1 interferons. The international journal of biochemistry & cell biology 45 15618008
2000 Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator. Endocrinology 45 10965917
2011 Structural basis of cooperative DNA recognition by the plasmid conjugation factor, TraM. Nucleic acids research 43 21565799
2012 Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PloS one 41 22970235
2007 The F plasmid-encoded TraM protein stimulates relaxosome-mediated cleavage at oriT through an interaction with TraI. Molecular microbiology 41 17238924
1998 Transfer protein TraM stimulates TraI-catalyzed cleavage of the transfer origin of plasmid R1 in vivo. Journal of molecular biology 41 9451441
1986 Origin of transfer of IncF plasmids and nucleotide sequences of the type II oriT, traM, and traY alleles from ColB4-K98 and the type IV traY allele from R100-1. Journal of bacteriology 41 3531163
2013 Inhibition of TLR4 signaling by TRAM-derived decoy peptides in vitro and in vivo. Journal of immunology (Baltimore, Md. : 1950) 40 23345333
2017 Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling. Biochemical Society transactions 39 28630139
2014 The TLR signaling adaptor TRAM interacts with TRAF6 to mediate activation of the inflammatory response by TLR4. Journal of leukocyte biology 38 24812060
2006 Absence of TRAM restricts Toll-like receptor 4 signaling in vascular endothelial cells to the MyD88 pathway. Circulation research 38 16574902
2006 Sec61alpha and TRAM are sequentially adjacent to a nascent viral membrane protein during its ER integration. Journal of molecular biology 38 17169373
2015 CD14, TLR4 and TRAM Show Different Trafficking Dynamics During LPS Stimulation. Traffic (Copenhagen, Denmark) 36 25707286
2007 Selective use of TRAM in lipopolysaccharide (LPS) and lipoteichoic acid (LTA) induced NF-kappaB activation and cytokine production in primary human cells: TRAM is an adaptor for LPS and LTA signaling. Journal of immunology (Baltimore, Md. : 1950) 36 17277119
2012 Inhibition of clathrin/dynamin-dependent internalization interferes with LPS-mediated TRAM-TRIF-dependent signaling pathway. Cellular immunology 35 22341560
2007 TRAM-34 inhibits nonselective cation channels. Pflugers Archiv : European journal of physiology 35 17318643
2012 Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model. American journal of respiratory cell and molecular biology 34 23204391
2023 TIRAP, TRAM, and Toll-Like Receptors: The Untold Story. Mediators of inflammation 33 36926280
2014 Inhibition of vascular calcification by block of intermediate conductance calcium-activated potassium channels with TRAM-34. Pharmacological research 33 24813858
2011 Membrane insertion and topology of the translocating chain-associating membrane protein (TRAM). Journal of molecular biology 33 21237175
2019 Tryptophan-kynurenine pathway attenuates β-catenin-dependent pro-parasitic role of STING-TICAM2-IRF3-IDO1 signalosome in Toxoplasma gondii infection. Cell death & disease 32 30770800
1991 Specific DNA binding of the TraM protein to the oriT region of plasmid R100. Journal of bacteriology 32 1917866
2021 Resolving monocytes generated through TRAM deletion attenuate atherosclerosis. JCI insight 31 34499622
2019 The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2. PLoS pathogens 31 30883606
2015 Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM. Journal of immunology (Baltimore, Md. : 1950) 31 25825441
1986 Cloning, mapping, and sequencing of plasmid R100 traM and finP genes. Journal of bacteriology 31 3522549
2020 TICAM2-related pathway mediates neutrophil exhaustion. Scientific reports 30 32873853
2012 TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88. PloS one 30 22685567
2004 Quorum-sensing antiactivator TraM forms a dimer that dissociates to inhibit TraR. Molecular microbiology 30 15186414
2011 TRAM (Transcriptome Mapper): database-driven creation and analysis of transcriptome maps from multiple sources. BMC genomics 29 21333005
2011 The immunoproteasomes regulate LPS-induced TRIF/TRAM signaling pathway in murine macrophages. Cell biochemistry and biophysics 29 21455681
2013 The small GTPase Arf6 is essential for the Tram/Trif pathway in TLR4 signaling. The Journal of biological chemistry 28 24297182
1993 TraM of plasmid R1 regulates its own expression. Molecular microbiology 28 8469119
2006 Hfq is a regulator of F-plasmid TraJ and TraM synthesis in Escherichia coli. Journal of bacteriology 27 16352828
2006 Protonation-mediated structural flexibility in the F conjugation regulatory protein, TraM. The EMBO journal 27 16710295
2004 Crystal structure of the quorum-sensing protein TraM and its interaction with the transcriptional regulator TraR. The Journal of biological chemistry 27 15044488
1991 The TraM protein of plasmid R1 is a DNA-binding protein. Molecular microbiology 27 2041477
1986 Nucleotide sequences of the R1-19 plasmid transfer genes traM, finP, traJ, and traY and the traYZ promoter. Journal of bacteriology 27 3009392
2002 Characterizing the DNA contacts and cooperative binding of F plasmid TraM to its cognate sites at oriT. The Journal of biological chemistry 26 11875064
2015 The effects of botulinum toxin A on survival of rat TRAM flap with vertical midline scar. Annals of plastic surgery 25 23817458
2007 Molecular basis of transcriptional antiactivation. TraM disrupts the TraR-DNA complex through stepwise interactions. The Journal of biological chemistry 25 17475619
1999 The essential transfer protein TraM binds to DNA as a tetramer. The Journal of biological chemistry 24 10601314
1985 The traM gene of the resistance plasmid R1: comparison with the corresponding sequence of the Escherichia coli F factor. Gene 24 2998939
2008 Exposure of rome city tram drivers to airborne platinum, rhodium, and palladium. Journal of occupational and environmental medicine 22 18849761
2001 Detection of recurrent breast cancer after TRAM flap reconstruction. Annals of plastic surgery 22 11756828
2008 Factor V Leiden mutation and thrombotic occlusion of microsurgical anastomosis after free TRAM flap. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 21 19022796
2016 Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain. Pediatric diabetes 20 27174668
2012 MyD88 or TRAM knockdown regulates interleukin (IL)-6, IL-8, and CXCL12 mRNA expression in human gingival and periodontal ligament fibroblasts. Journal of periodontology 20 23136947