TP14: The role of the proinflammatory protein kinases IKKε and TBK1 for cell proliferation and tumor development

There is increasing evidence for a critical role of the NF-κB transcription factor network for initiation and promotion of tumors. The central step of NF-kB activation is the IKK-mediated phosphorylation of IκB, which is the prerequisite for subsequent proteasome/ubiquitin-mediated degradation of Iκ B. Cells do not only contain the canonical IKK complex, but also the so-called non-canonical IKK complex which consists of the two kinases IKKε and TBK1 (TANK-binding kinase) as well as adapter proteins such as TANK. The non-canonical IKKs are dispensable for IkB phosphorylation but instead are important for the control of nuclear NF-κB activity and for the activation of transcription factors IRF3/7, as schematically shown in the figure. Recent evidence points to an important role of the non-canonical IKK complex for the development of solid cancers. The expression of both kinases is frequently deregulated in solid tumors such as breast cancer (IKKε) and KRAS-driven cancers (TBK1).

The research plan consists of three different parts. In the first part it is planned to investigate the molecular mechanisms regulating the function of IKKε and TBK1. The activating signals, interacting proteins and phosphorylation substrates of both kinases are identified in unbiased screens. This part will generate important experimental tools and informations that will feed in another experimental part. The wildtype kinases, adequate mutants and phosphorylation substrates are tested for their contribution to oncogenic transformation of cells and their relevance for the pro-proliferative functions of IKKε and TBK1. We will also determine the expression levels and intracellular localization of IKKε and TBK1 in tumor samples. In the third part we will develop adequate mouse models to study the functional consequences of IKKε/TBK1 overexpression for the induction and promotion of tumors.