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Details on Person TANK-binding kinase I (TBK1) and its close homolog inhibitor...

Class:IdSummation:9823911
_displayNameTANK-binding kinase I (TBK1) and its close homolog inhibitor...
_timestamp2024-02-28 22:54:38
created[InstanceEdit:9823907] Shamovsky, Veronica, 2023-01-12
literatureReference[LiteratureReference:5362581] Crystal structure and mechanism of activation of TANK-binding kinase 1
[LiteratureReference:433854] Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation
[LiteratureReference:433880] Involvement of the ubiquitin-like domain of TBK1/IKK-i kinases in regulation of IFN-inducible genes
[LiteratureReference:5362611] Structure and ubiquitination-dependent activation of TANK-binding kinase 1
[LiteratureReference:9827948] The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing
[LiteratureReference:9705328] IKKε-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex
[LiteratureReference:165917] The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection
[LiteratureReference:166859] IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway
[LiteratureReference:202505] Regulation and function of IKK and IKK-related kinases
modified[InstanceEdit:9823946] Shamovsky, Veronica, 2023-01-12
[InstanceEdit:9832588] Shamovsky, Veronica, 2023-04-03
[InstanceEdit:9832589] Shamovsky, Veronica, 2023-04-03
[InstanceEdit:9839313] Shamovsky, Veronica, 2023-07-05
[InstanceEdit:9839731] Shamovsky, Veronica, 2023-07-10
[InstanceEdit:9863311] Shamovsky, Veronica, 2024-02-28
[InstanceEdit:9863317] Shamovsky, Veronica, 2024-02-28
textTANK-binding kinase I (TBK1) and its close homolog inhibitor of kappaB kinase epsilon (IKKε or IKBKE) are serine/threonine protein kinases, that are activated by pattern-recognition receptors upon infection. Activity of both TBK1 and IKKε (IKBKE) is regulated by the phosphorylation of a serine residue 172 (S172) within the activation loop of the N-terminal kinase domain (KD) (Clark et al., 2009). The activation of TBK1 and IKKε may occur through autophosphorylation or via activity of a distinct protein kinase (Clark et al., 2009). Structural studies of TBK1 reveal a dimeric assembly which is mediated by several interfaces involving an N-terminal KD, a ubiquitin-like domain (ULD), and an alpha-helical scaffold dimerization domain (SDD) of TBK1 thus supporting a model of trans-autophosphorylation (Larabi A et al., 2013; Tu D et al., 2013). The ULD of TBK1 (and IKBKE) is involved in the control of kinase activation, substrate presentation and downstream signaling (Ikeda F et al., 2007; Tu D et al., 2013). Upon activation, TBK1 is modified by K63-linked polyubiquitination on lysines 30 (K30) and K401 (Tu D et al., 2013). Ubiquitination of TBK1 leads to conformational changes that facilitate activation of the KD while maintaining the overall dimer conformation (Larabi A et al., 2013). The ubiquitination and phosphorylation sites, as well as dimer contacts, are conserved in the close homolog IKKε (IKBKE) suggesting that both kinases are regulated through similar activation mechanisms (Tu D et al., 2013; Zhou AY et al., 2013). Activated TBK1 then phosphorylates IRF3 and IRF7.

TBK1, K63‑polyubiquitinated on K30 and K401, interacts with ubiquitin-binding adaptor protein optineurin (OPTN), which regulates the activity of TBK1 (Pourcelot M et al., 2016).

This Reactome event shows TBK1 phosphorylation within the activated TLR4 complex.

(summation)[Reaction:9823906] TBK1 is phosphorylated within the activated TLR4 complex [Homo sapiens]
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