Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Toll-Like Receptor Pathway 1
Mus musculus
Category:
Protein Pathway
Sub-Categories:
Immunological
Pathogen-Activated Signaling
Gene Regulatory
Cellular Response
Created: 2018-09-20
Last Updated: 2019-08-16
Toll-like receptors (TLRs) are part of the innate immune system. These receptors recognize pathogen-associated molecular patterns from different microbes. TLR2 recognizes a variety of PAMPs including lipoproteins, peptidoglycans, lipotechoic acids, and mannan. TLR3 recognizes viral double-stranded RNA, small interfering RNAsa, and self-RNAs. TLR4 recognizes lipopolysaccharides. TLR7 recognizes single-stranded RNA. TLR9 recognizes bacterial and viral DNA with unmethylated CpG-DNA motifs. TLRs are synthesized in the endoplasmic reticulum, moved to the Golgi, and then recruited to the cell surface or intracellular compartments. TLRs recruit adaptor molecules such as MYD88, TRIF, TIRAP, or TRAM leading to the activation of transcription factors NF-kappa-B causing innate immune responses. MYD88 is recruited by all TLRs. Adaptor TIRAP recruits MYD88 to cell surface TLRs, including TLR2 and TLR4. TLR signaling molecule IRAK1 activation activates TRAF6 causing the activation of IKK complex then NF-kappa-B and kinases. Activated TRAF6 promotes polyubiquination of TRAF6 and TAK1, TAB1, TAB2 complex. TAK1 activates pathways causing activation of IKK complex and NF-kappa-B and MAPK pathways. The IKK complex phosphorylates and activates IKK-beta. IKK complex also phosphorylates I-kappa-B-alpha allowing dissociation and translocation of NF-kappa-B to the nucleus resulting in proinflammatory gene expression. Activated TAK1 complex also activates p38 and JNK, regulating the activation of AP-1 transcription factors to regulate inflammatory responses. Many transmembrane molecules, such as glycophosphatidylinositol-anchored protein CD14, also regulate TLR signaling pathways.
References
Toll-Like Receptor Pathway 1 References
Ghosh S, Gifford AM, Riviere LR, Tempst P, Nolan GP, Baltimore D: Cloning of the p50 DNA binding subunit of NF-kappa B: homology to rel and dorsal. Cell. 1990 Sep 7;62(5):1019-29. doi: 10.1016/0092-8674(90)90276-k.
Pubmed: 2203532
Inoue J, Kerr LD, Kakizuka A, Verma IM: I kappa B gamma, a 70 kd protein identical to the C-terminal half of p110 NF-kappa B: a new member of the I kappa B family. Cell. 1992 Mar 20;68(6):1109-20. doi: 10.1016/0092-8674(92)90082-n.
Pubmed: 1339305
Gerondakis S, Morrice N, Richardson IB, Wettenhall R, Fecondo J, Grumont RJ: The activity of a 70 kilodalton I kappa B molecule identical to the carboxyl terminus of the p105 NF-kappa B precursor is modulated by protein kinase A. Cell Growth Differ. 1993 Aug;4(8):617-27.
Pubmed: 8398903
Martin JH, Mohit AA, Miller CA: Developmental expression in the mouse nervous system of the p493F12 SAP kinase. Brain Res Mol Brain Res. 1996 Jan;35(1-2):47-57. doi: 10.1016/0169-328x(95)00181-q.
Pubmed: 8717339
Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto KI: JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol. 1999 Nov;19(11):7539-48. doi: 10.1128/mcb.19.11.7539.
Pubmed: 10523642
Yang DD, Kuan CY, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Rakic P, Flavell RA: Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature. 1997 Oct 23;389(6653):865-70. doi: 10.1038/39899.
Pubmed: 9349820
Matsuura K, Setoguchi M, Nasu N, Higuchi Y, Yoshida S, Akizuki S, Yamamoto S: Nucleotide and amino acid sequences of the mouse CD14 gene. Nucleic Acids Res. 1989 Mar 11;17(5):2132. doi: 10.1093/nar/17.5.2132.
Pubmed: 2467257
Setoguchi M, Nasu N, Yoshida S, Higuchi Y, Akizuki S, Yamamoto S: Mouse and human CD14 (myeloid cell-specific leucine-rich glycoprotein) primary structure deduced from cDNA clones. Biochim Biophys Acta. 1989 Jul 7;1008(2):213-22. doi: 10.1016/0167-4781(80)90012-3.
Pubmed: 2472171
Ferrero E, Hsieh CL, Francke U, Goyert SM: CD14 is a member of the family of leucine-rich proteins and is encoded by a gene syntenic with multiple receptor genes. J Immunol. 1990 Jul 1;145(1):331-6.
Pubmed: 1694207
Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, Aderem A: The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999 Oct 21;401(6755):811-5. doi: 10.1038/44605.
Pubmed: 10548109
Yokoyama R, Itoh S, Kamoshida G, Takii T, Fujii S, Tsuji T, Onozaki K: Staphylococcal superantigen-like protein 3 binds to the Toll-like receptor 2 extracellular domain and inhibits cytokine production induced by Staphylococcus aureus, cell wall component, or lipopeptides in murine macrophages. Infect Immun. 2012 Aug;80(8):2816-25. doi: 10.1128/IAI.00399-12. Epub 2012 Jun 4.
Pubmed: 22665377
Heine H, Kirschning CJ, Lien E, Monks BG, Rothe M, Golenbock DT: Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin. J Immunol. 1999 Jun 15;162(12):6971-5.
Pubmed: 10358136
Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE: The cloning and characterization of human MyD88: a member of an IL-1 receptor related family. FEBS Lett. 1997 Jan 27;402(1):81-4. doi: 10.1016/s0014-5793(96)01506-2.
Pubmed: 9013863
Hardiman G, Jenkins NA, Copeland NG, Gilbert DJ, Garcia DK, Naylor SL, Kastelein RA, Bazan JF: Genetic structure and chromosomal mapping of MyD88. Genomics. 1997 Oct 15;45(2):332-9. doi: 10.1006/geno.1997.4940.
Pubmed: 9344657
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Reichwald K, Thiesen J, Wiehe T, Weitzel J, Poustka WA, Rosenthal A, Platzer M, Stratling WH, Kioschis P: Comparative sequence analysis of the MECP2-locus in human and mouse reveals new transcribed regions. Mamm Genome. 2000 Mar;11(3):182-90.
Pubmed: 10723722
Church DM, Goodstadt L, Hillier LW, Zody MC, Goldstein S, She X, Bult CJ, Agarwala R, Cherry JL, DiCuccio M, Hlavina W, Kapustin Y, Meric P, Maglott D, Birtle Z, Marques AC, Graves T, Zhou S, Teague B, Potamousis K, Churas C, Place M, Herschleb J, Runnheim R, Forrest D, Amos-Landgraf J, Schwartz DC, Cheng Z, Lindblad-Toh K, Eichler EE, Ponting CP: Lineage-specific biology revealed by a finished genome assembly of the mouse. PLoS Biol. 2009 May 5;7(5):e1000112. doi: 10.1371/journal.pbio.1000112. Epub 2009 May 26.
Pubmed: 19468303
Trofimova M, Sprenkle AB, Green M, Sturgill TW, Goebl MG, Harrington MA: Developmental and tissue-specific expression of mouse pelle-like protein kinase. J Biol Chem. 1996 Jul 26;271(30):17609-12. doi: 10.1074/jbc.271.30.17609.
Pubmed: 8663605
Ishida T, Mizushima Si, Azuma S, Kobayashi N, Tojo T, Suzuki K, Aizawa S, Watanabe T, Mosialos G, Kieff E, Yamamoto T, Inoue J: Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem. 1996 Nov 15;271(46):28745-8. doi: 10.1074/jbc.271.46.28745.
Pubmed: 8910514
Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C, Kodzius R, Shimokawa K, Bajic VB, Brenner SE, Batalov S, Forrest AR, Zavolan M, Davis MJ, Wilming LG, Aidinis V, Allen JE, Ambesi-Impiombato A, Apweiler R, Aturaliya RN, Bailey TL, Bansal M, Baxter L, Beisel KW, Bersano T, Bono H, Chalk AM, Chiu KP, Choudhary V, Christoffels A, Clutterbuck DR, Crowe ML, Dalla E, Dalrymple BP, de Bono B, Della Gatta G, di Bernardo D, Down T, Engstrom P, Fagiolini M, Faulkner G, Fletcher CF, Fukushima T, Furuno M, Futaki S, Gariboldi M, Georgii-Hemming P, Gingeras TR, Gojobori T, Green RE, Gustincich S, Harbers M, Hayashi Y, Hensch TK, Hirokawa N, Hill D, Huminiecki L, Iacono M, Ikeo K, Iwama A, Ishikawa T, Jakt M, Kanapin A, Katoh M, Kawasawa Y, Kelso J, Kitamura H, Kitano H, Kollias G, Krishnan SP, Kruger A, Kummerfeld SK, Kurochkin IV, Lareau LF, Lazarevic D, Lipovich L, Liu J, Liuni S, McWilliam S, Madan Babu M, Madera M, Marchionni L, Matsuda H, Matsuzawa S, Miki H, Mignone F, Miyake S, Morris K, Mottagui-Tabar S, Mulder N, Nakano N, Nakauchi H, Ng P, Nilsson R, Nishiguchi S, Nishikawa S, Nori F, Ohara O, Okazaki Y, Orlando V, Pang KC, Pavan WJ, Pavesi G, Pesole G, Petrovsky N, Piazza S, Reed J, Reid JF, Ring BZ, Ringwald M, Rost B, Ruan Y, Salzberg SL, Sandelin A, Schneider C, Schonbach C, Sekiguchi K, Semple CA, Seno S, Sessa L, Sheng Y, Shibata Y, Shimada H, Shimada K, Silva D, Sinclair B, Sperling S, Stupka E, Sugiura K, Sultana R, Takenaka Y, Taki K, Tammoja K, Tan SL, Tang S, Taylor MS, Tegner J, Teichmann SA, Ueda HR, van Nimwegen E, Verardo R, Wei CL, Yagi K, Yamanishi H, Zabarovsky E, Zhu S, Zimmer A, Hide W, Bult C, Grimmond SM, Teasdale RD, Liu ET, Brusic V, Quackenbush J, Wahlestedt C, Mattick JS, Hume DA, Kai C, Sasaki D, Tomaru Y, Fukuda S, Kanamori-Katayama M, Suzuki M, Aoki J, Arakawa T, Iida J, Imamura K, Itoh M, Kato T, Kawaji H, Kawagashira N, Kawashima T, Kojima M, Kondo S, Konno H, Nakano K, Ninomiya N, Nishio T, Okada M, Plessy C, Shibata K, Shiraki T, Suzuki S, Tagami M, Waki K, Watahiki A, Okamura-Oho Y, Suzuki H, Kawai J, Hayashizaki Y: The transcriptional landscape of the mammalian genome. Science. 2005 Sep 2;309(5740):1559-63. doi: 10.1126/science.1112014.
Pubmed: 16141072
This pathway was propagated using PathWhiz -
Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0063899
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings