TIRAP is phosphorylated by BTK

Stable Identifier
R-HSA-2201322
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Neisseria meningitidis serogroup B, Chlamydia trachomatis
Compartment
Synonyms
MAL is phosphorylated by BTK
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Upon activation of TLR2/or 4 signaling pathway TIRAP(MAL), a TIR domain–containing adapter protein, undergoes tyrosine phosphorylation (Piao W et al. 2008; Gray P et al. 2006). Bruton's tyrosine kinase (BTK) was shown to mediate the TIRAP phosphorylation (Jefferies CA et al. 2003; Gray P et al. 2006). BTK-specific inhibitor, LFM-A13, blocked the phosphorylation of TIRAP in human monocytic cell line THP-1 stimulated with LPS or macrophage-activating lipopeptide-2 (MALP-2) (Gray P et al. 2006). LFM-A13 also inhibited activation of NFkappaB in LPS-treated THP-1 (Jefferies CA et al. 2003). Besides BTK kinase TIRAP was shown to associate with other kinases such as protein kinase C delta (PKC delta) suggesting their regulatory role in TIRAP activation (Kubo-Murai M et al. 2007).

Tyr-86, Tyr-106 and Tyr-187 were identified as possible phosphorylation sites (Gray P et al. 2006). An additional study has shown that Tyr-86, Tyr-106, and Tyr-159 are important residues, as mutagenesis of these residues impaired TIRAP (MAL) phosphorylation, affected its interaction with BTK and also impaired downstream signaling (Piao W et al. 2008). BTK-mediated phosphorylation of TIRAP leads to recruitment of suppressor of cytokine signaling 1 (SOCS1), which assembles K48-linked polyubiquitin chains resulting in TIRAP's proteosomal degradation, disrupting the TLR complex, and terminating signaling (Mansell A et al. 2006). TIRAP function is also regulated by the cysteine protease caspase-1, which cleaves the protein in a region of the molecule that interacts with MyD88 and TLR4 (Ulrichts P et al. 2010).

Literature References
PubMed ID Title Journal Year
18070880 Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance

Piao, W, Song, C, Chen, H, Wahl, LM, Fitzgerald, KA, O'Neill, LA, Medvedev, AE

J Biol Chem 2008
12724322 Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4

Jefferies, CA, Doyle, S, Brunner, C, Dunne, A, Brint, E, Wietek, C, Walch, E, Wirth, T, O'Neill, LA

J Biol Chem 2003
16439361 MyD88 adapter-like (Mal) is phosphorylated by Bruton's tyrosine kinase during TLR2 and TLR4 signal transduction

Gray, P, Dunne, A, Brikos, C, Jefferies, CA, Doyle, SL, O'Neill, LA

J Biol Chem 2006
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein tyrosine kinase activity of TIRAP:PI(4,5)P2:BTK:activated TLR2/4 [plasma membrane]
Physical Entity
Activity
Authored
Reviewed
Created