TICAM1

'''TIR domain containing adaptor molecule 1''' ('''TICAM1'''; formerly known as '''TIR-domain-containing adapter-inducing interferon-β''' or '''TRIF''') is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.<ref name=PalssonMcDermottONeill2004>{{cite journal|last1=Palsson-McDermott|first1=Eva M.|last2=O'Neill|first2=Luke A. J.|authorlink2=Luke A. J. O'Neill|title=Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4|journal=Immunology|volume=113|issue=2|year=2004|pages=153–162|pmid=15379975|doi=10.1111/j.1365-2567.2004.01976.x|pmc=1782563}} {{open access}}</ref>

Toll-like receptors (TLRs) recognize specific components of microbial invaders and activate an immune response to these pathogens. After these receptors recognize highly conserved pathogenic patterns, a downstream signaling cascade is activated in order to stimulate the release of inflammatory cytokines and chemokines as well as to upregulate the expression of immune cells. All TLRs have a TIR domain that initiates the signaling cascade through TIR adapters. Adapters are platforms that organize downstream signaling cascades leading to a specific cellular response after exposure to a given pathogen.<ref>{{cite journal |vauthors=Guo B, Cheng G |title=Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK |journal=J. Biol. Chem. |volume=282 |issue=16 |pages=11817–26 |year=2007 |pmid=17327220 |doi=10.1074/jbc.M700017200|doi-access=free }}</ref>

== Structure == TICAM1 is primarily active in the spleen and is often regulated when MyD88 is deficient in the liver, indicating organ-specific regulation of signaling pathways. Curiously, there is a lack of redundancy within the TLR4 signaling pathway that leads to microbial evasion of immune response in the host after mutations occur within intermediates of the pathway.<ref>Palsson-McDermott, Eva and Luke A J O’Neill (2004) Immunology. 113(2) 153-162</ref> Three TRAF-binding motifs present in the amino terminal region of TICAM1 are necessary for association with TRAF6. Destruction of these motifs reduced the activation of NF-κB, a transcription factor that is also activated by the carboxy-terminal domain of TICAM1 in the upregulation of cytokines and co-stimulatory immune molecules. This domain recruits receptor-interacting protein (RIP1) and RIP3 through the RIP homotypic interaction motif. Cells deficient for RIP1 gene display attenuated TLR3 activation of NF-κB, indicating the use of the RIP1 gene in downstream TICAM1 activation, in contrast to other TLRs that use IRAK protein for the activation of NF-κB.<ref>Kawai, Taro and Shizuo Akira. (2004). Arthritis Res. Ter. 7(1) 12-19</ref>

== Areas of research == Investigations into the function of TICAM1 are of great significance to various fields of biomedical research. The pathogenesis of infectious disease, septic shock, tumor growth, and rheumatoid arthritis all have close ties with TLR signaling pathways, specifically to that of TICAM1 . Better understanding of the TICAM1 pathway will be therapeutically useful in the development of vaccines and treatments that can control associated inflammation and antiviral responses. Experiments involving wild-type and TICAM1-deficient mice are critical for understanding the coordinated responses of TLR pathways. It is necessary to study the coordinated effects of these pathways in order to understand the complex responses initiated by TICAM1.<ref>{{cite journal |vauthors=Ouyang X, Negishi H, Takeda R, Fujita Y, Taniguchi T, Honda K |title=Cooperation between MyD88 and TICAM1 pathways in TLR synergy via IRF5 activation |journal=Biochem. Biophys. Res. Commun. |volume=354 |issue=4 |pages=1045–51 |year=2007 |pmid=17275788 |doi=10.1016/j.bbrc.2007.01.090}}</ref>

== References == {{Reflist|2}}

==External links== * [http://www.genome.ad.jp/dbget-bin/www_bget?path:ko04620 Toll-like receptor signaling pathway - Reference pathway (KO)] from the KEGG website. * {{MeshName|TICAM1+protein,+human}} {{TLR signaling pathway}}

Category:Immune system