Roles for the IKK-Related Kinases TBK1 and IKKε in Cancer

Abstract

While primarily studied for their roles in innate immune response, the IκB kinase (IKK)-related kinases TANK-binding kinase 1 (TBK1) and IKKε also promote the oncogenic phenotype in a variety of cancers. Additionally, several substrates of these kinases control proliferation, autophagy, cell survival, and cancer immune responses. Here we review the involvement of TBK1 and IKKε in controlling different cancers and in regulating responses to cancer immunotherapy.

Keywords: IKKε; KRAS; TBK1; autophagy; cancer signaling; innate immunity.

Figure 1

Functional effects of the IκB kinase (IKK)-related kinases. In addition to immune responses, IKKε and TANK-binding kinase 1 (TBK1) are important signaling proteins for critical cellular processes associated with cancer. For more information see text. Adapted from [19].

Figure 2

Structural comparison of IKK-related kinases. (A). The kinase domain of IKKε shares 27% identity with IKKα and 24% identity with IKKβ. TBK1 shares 49% identity and 65% similarity with IKKε. (B). Surface views of TBK1 (left panels) and IKKβ (right panels), with corresponding domains colored in TBK1 and IKKβ. In TBK1, the ULDs bridge between dimer SDDs, but extend away from the opposite SDDs in IKKβ. The kinase domains in the IKKβ dimer are differently oriented and do not form dimer contacts. The IKKβ structure is drawn from Protein Data Bank ID code 3QA8 [28]. The TBK1 structure is drawn from Protein Data Bank ID code 4IM0 [29]. TBK1, TANK-binding kinase 1; IKK, IκB kinase; KD, kinase domain; ULD, ubiquitin-like domain; SDD, scaffold dimerization domain; NBD, NEMO-binding domain. Adapted from [5,29,30].

Figure 3

TANK-binding kinase 1 (TBK1) and IκB kinase epsilon (IKKε) control Akt phosphorylation and its activity (in some settings), which drives mechanistic target of rapamycin complex 1 (mTORC1) activity. TBK1 is also reported to directly phosphorylate mTOR. See text.