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. 2006;2:2006.0015.
doi: 10.1038/msb4100057. Epub 2006 Apr 18.

A Comprehensive Map of the Toll-Like Receptor Signaling Network

Free PMC article

A Comprehensive Map of the Toll-Like Receptor Signaling Network

Kanae Oda et al. Mol Syst Biol. .
Free PMC article


Recognition of pathogen-associated molecular signatures is critically important in proper activation of the immune system. The toll-like receptor (TLR) signaling network is responsible for innate immune response. In mammalians, there are 11 TLRs that recognize a variety of ligands from pathogens to trigger immunological responses. In this paper, we present a comprehensive map of TLRs and interleukin 1 receptor signaling networks based on papers published so far. The map illustrates the possible existence of a main network subsystem that has a bow-tie structure in which myeloid differentiation primary response gene 88 (MyD88) is a nonredundant core element, two collateral subsystems with small GTPase and phosphatidylinositol signaling, and MyD88-independent pathway. There is extensive crosstalk between the main bow-tie network and subsystems, as well as feedback and feedforward controls. One obvious feature of this network is the fragility against removal of the nonredundant core element, which is MyD88, and involvement of collateral subsystems for generating different reactions and gene expressions for different stimuli.


Figure 1
Figure 1
A comprehensive molecular interaction map of TLR signaling network. The SBML and PDF files of the map are available from the Supplementary information. The map can be best viewed in the PDF format. All of the species, proteins, and reactions included in the map are listed in the SBML file when opened by CellDesigner ( Abbreviations: A20, tumor necrosis factor-inducible protein A20; Akt, v-akt murine thymoma viral oncogene homolog; ASK, apoptosis signal-regulating kinase; ATF, activating transcription factor; Bcl, B-cell CLL/lymphoma; beta-TrCP, beta-transducin repeat-containing protein; BTK, Bruton agammaglobulinemia tyrosine kinase; CaM, calmodulin; CaMKI, calcium/calmodulin-dependent protein kinase; CBP, CREB-binding protein; c-Cbl, Casitas B-lineage lymphoma proto-oncogene; CD, cluster of differentiation; Cdc42, cell division cycle 42 (GTP-binding protein, 25 kDa); CK, casein kinase; c-Myc, v-myc myelocytomatosis viral oncogene homolog; CRE, cAMP response element; CREB, cAMP response element-binding protein; CsgA, major curlin subunit precursor, Salmonella enterica; c-Src, v-src sarcoma (Schmidt–Ruppin A-2) viral oncogene homolog (avian); C-TAK1, MAP/microtubule affinity-regulating kinase 3; CYLD, cylindromatosis (turban tumor syndrome); DAG, diacylglycerol; dsRNA, double-strand RNA; ECSIT, evolutionarily conserved signaling intermediate in toll pathway; EEA, early endosome antigen; eIF, eukaryotic translation initiation factor; Elk-1, ETS domain protein Elk-1; ERK, extracellular signal-regulated kinase; FADD, Fas-associated via death domain; Fos, v-fos FBJ murine osteosarcoma viral oncogene homolog; gp91phox, glycoprotein of 91 kDa from phagocyte oxidase; GSK, glycogen synthase kinase; HDAC, histone deacetylase, HMG, high-mobility group nucleosome-binding domain; hnRNP, heterogeneous nuclear ribonucleoprotein; HSP, heat-shock protein; Ibtk, inhibitor of Bruton agammaglobulinemia tyrosine kinase; ICE, interleukin 1-B-converting enzyme; IκB, nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor; IKK, I-κ-B kinase; IL, interleukin; IL-1ra, interleukin 1 receptor antagonist; IL-1RAcP, interleukin 1 receptor accessory protein; IP3, inositol 1,4,5-triphosphate; IP3R, inositol 1,4,5-triphosphate receptor; IRAK, interleukin 1 receptor-associated kinase; IRF, interferon-regulatory factor; ISRE, interferon-a-stimulated response element; JNK, c-Jun N-terminal kinase; Jun, v-jun sarcoma virus 17 oncogene homolog (avian); KSR, kinase suppressor of ras; LBP, lipopolysaccharide-binding protein; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MAPKAPK, mitogen-activated protein kinase-activated protein kinase; MBP, myelin basic protein; MD-2, lymphocyte antigen 96; MEKK, MAPK/ERK kinase kinase; MKK, mitogen-activated protein kinase kinase; MKP, MAP kinase phosphatase; MMT virus, mouse mammary tumor virus; Mnk, MAP kinase interacting serine/threonine kinase; MSK, mitogen- and stress-activated protein kinase; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor κB; NIK, nuclear factor κB-inducing kinase; NOD, nucleotide-binding oligomerization domain; NSF, N-ethylmaleimide-sensitive factor; NUR77, nuclear receptor subfamily 4, group A, member 1; p62, phosphotyrosine-independent ligand for the Lck SH2 domain p62; PAK, p21-activated kinase; PDK, 3-phosphoinositide-dependent protein kinase; pellino, pellino (Drosophila) homolog; PI(4)P5K, phosphatidylinositol-5-kinase; PI, phosphatidylinositol; Pi, phosphoric ion; PI3,4,5-P3, phosphatidylinositol-3,4,5-triphosphate; PI3,4-P2, phosphatidylinositol-3,4-bisphosphate; PI3K, phosphatidylinositol-3-kinase; PI3-P, phosphatidylinositol-3-phosphate; PI4,5-P2, phosphatidylinositol-4,5-bisphosphate; PI4-P, phosphatidylinositol-4-phosphate; PKA, protein kinase A; PKC, protein kinase C; PKR, eukaryotic translation initiation factor 2-α kinase; PLC, phospholipase C; PLD, phospholipase D; PP, protein phosphatase; Rab, RAS-associated protein; Rabaptin, RAB GTPase-binding effector protein; Rabex, RAB guanine nucleotide exchange factor; Rac, ras-related C3 botulinum toxin substrate; Raf, v-raf-1 murine leukemia viral oncogene homolog; Ras, rat sarcoma viral oncogene homolog; Rho, ras homolog gene family; RhoGDI, GDP dissociation inhibitor; Rin, Ras interaction; RIP, receptor-interacting serine–threonine kinase; RKIP, Raf kinase inhibitor protein; RS virus, respiratory syncytial virus; Sab, SH3-domain-binding protein 5 (BTK-associated); SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; SIGIRR, single immunoglobulin and toll-interleukin 1 receptor (TIR) domain; SOCS, suppressor of cytokine signaling; ssRNA, single-strand RNA; ST2L, interleukin 1 receptor-like 1; STF, soluble tuberculosis factor; TAB, transforming growth factor beta-activated kinase-binding protein; TAK, transforming growth factor beta-activated kinase; TBK, TRAF family member-associated nuclear factor κB activator-binding kinase; TICAM, toll-like receptor adaptor molecule; TIFA, TRAF-interacting protein with a forkhead-associated domain; TIR, toll-interleukin 1 receptor; TIRAP, toll-interleukin 1 receptor domain-containing adaptor protein; TLR, toll-like receptor; TOLLIP, toll-interacting protein; TPL, tumor progression locus; TRAF, tumor necrosis factor receptor-associated factor; TRAILR, tumor necrosis factor-related apoptosis-inducing ligand receptor; TRIAD3A, ubiquitin-conjugating enzyme 7-interacting protein 1, isoform A; TRIP, thyroid hormone receptor interactor; Trx, thioredoxin; Ubc, ubiquitin-conjugating enzyme; Uev, ubiquitin-conjugating enzyme E2 variant; Vav1, vav 1 oncogene.
Figure 2
Figure 2
The architecture of the TLR signaling network. A reduced map of TLR signaling network that extracts the flow of activation and inhibition. This diagram is created based on the comprehensive TLR signaling network map as shown in Figure 1. Filled arrows in this figure indicate ‘activation', and other arrows such as bar-headed, circle-headed, dashed, and dot-dot-dashed lines are the same as Figure 1. The double line denotes ‘binding' in this figure. A molecule shown to connect with both ‘activation' and ‘inhibition' arrows can act oppositely according to the condition. A line of mutual inhibition that connects two CREB-binding protein (CBP) molecules means the competition for limiting amounts of CBP, which is a transcriptional coactivator that interacts with both NF-κ B p65 and CREB. TLR signaling network consists of the main bow-tie network and three collateral subnetworks that involves small GTPase, PIPs, and MyD88-independent pathways. There are extensive crosstalk regulations between the main bow-tie network and other subsystems, as well as multiple feedback and feedforward controls. Notable interactions are color-coded: red, positive feedback loop; blue, negative feedback loop; purple, inhibitory feedforward path; orange, positive crosstalk from subsystems to the bow-tie network; and green, negative crosstalk from subsystems to the bow-tie network. High resolution file for this figure is available from the Supplementary information.
Figure 3
Figure 3
The core of bow-tie networks may have ‘classifier hyperspace' where reactions to various inputs can be classified within subregions within the hyperspace that consists of activation levels of core elements of the bow-tie structure. (A) EGFR signaling and GPCR signaling network has a small numbers of core elements such as small GTPases, PIPs, and non-RTKs for EGFR signaling, and calcium, cAMP, and inositol phosphate for GPCR signaling. For example, a group of stimuli may all activate core elements in the way that can be classified into region C1, for example, and these stimuli triggers transcription of genes and physiological responses as denoted as C1. (B) TLR signaling network has a salient feature where possible bow-tie core is composed of a single element, MyD88, thus there is no classifier hyperspace created within the bow-tie network. Differences of responses against various stimuli are modulated by the activation of elements in collateral pathways, such as small GTPases, PIPs, and TICAM1 involved in MyD88-independent pathway, and MyD88 pathway essentially calibrates the whole network. Thus, for TLR signaling network, the classifier hyperspace has four dimensions.

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