Molecular mechanisms of neurodegeneration and cancer

Previous and current research
The JNK family of MAP kinases are causally involved in neurodegeneration and cancer, two clinically important human diseases. We have shown previously using conditional mutagenesis and knock-in approaches in mice that the transcription factor c-Jun is the essential substrate of JNK signalling in both processes.

To investigate the mechanism of JNK/c-Jun-mediated transcriptional regulation in disease, we have identified proteins that preferentially interact with N-terminally phosphorylated c-Jun (Phosphorylation-dependent c-Jun) interactor (PDJs) or that bind preferentially to the unphosphorylated form of c-Jun. We have shown that the PDJs, which includes the tumour suppressor Fbw7 and the transcription factor TCF4, are novel disease-relevant modulators of JNK signalling. The identification of PDJs suggests that JNK/c-Jun signalling is interpreted by proteins interacting with c-Jun in a phosphorylation-dependent manner, providing a conceptual framework that can explain signal strength- and cell type-dependent differences in the biological effects of JNK signalling.

Future projects
Currently we are using a combination of biochemical methods and mouse genetics to validate and study the function of the JNK/cJun/PDJ pathway in disease.

We are generating various MAP kinase, c-Jun and PDJ mouse models that are used to investigate the epistatic relationship and functional dependency of pathway components and may allow the delineation of molecular pathways controlling neurodegeneration and cancer. Due to their ability to modulate and direct the physiological outcome of JNK signalling and c-Jun activation, PDJs will have significant therapeutic potential.