Reactome | TBK1 is phosphorylated within STING:TBK1:STAT6 complex

TBK1 is phosphorylated within STING:TBK1:STAT6 complex

Stable Identifier

R-HSA-3249390

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, cytoplasmic vesicle membrane

ReviewStatus

5/5

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TBK1 is phosphorylated within STING:TBK1:STAT6 complex

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Here we show that the activation of TBK1 occurs via an autophosphorylation event, although there is no direct evidence for TBK1 phosphorylation in STAT6-mediated signaling. TBK1 activity is regulated by phosphorylation of Ser-172 within the kinase activation loop [Kishore N et al 2002]. TBK1 phosphorylation is thought to be an autoactivation event. Biochemical analysis demonstrated that the kinase domain alone was sufficient to fully autoactivate TBK1 and was capable of phosphorylating both macromolecular and peptide substrates [Ma X et al 2012]. Furthermore, TBK1 can autophosphorylate at Ser-172 and autoactivate when overexpressed in HEK293 cells. Additionally, in co-transfection experiments wild type TBK1 associated with and phosphorylated the catalytically inactive mutant TBK1-(K38A) at Ser-172 [Clark K et al 2009]. Studies of the crystal structure of TBK1 in complex with a potent small-molecule inhibitor BX795 revealed that Ser-172 from one protomer is located in close proximity to the active site of the neighboring protomer, providing a snapshot of a potential transautoactivation reaction intermediate [Ma X et al 2012]. However, involvement of a distinct upstream activating kinase in the TBK1 phosphorylation should not be ruled out [Clark K et al 2009].

Literature References

PubMed ID	Title	Journal	Year
22619329	Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation Ma, X, Helgason, E, Phung, QT, Quan, CL, Iyer, RS, Lee, MW, Bowman, KK, Starovasnik, MA, Dueber, EC	Proc. Natl. Acad. Sci. U.S.A.	2012
11839743	IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2 Kishore, N, Huynh, QK, Mathialagan, S, Hall, T, Rouw, S, Creely, D, Lange, G, Caroll, J, Reitz, B, Donnelly, A, Boddupalli, H, Combs, RG, Kretzmer, K, Tripp, CS	J. Biol. Chem.	2002
19307177	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 Clark, K, Plater, L, Peggie, M, Cohen, P	J Biol Chem	2009
22394562	STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway Tanaka, Y, Chen, ZJ	Sci Signal	2012