Abstract

The c-Jun N-terminal Kinase (JNK) was originally identified as a mediator of stress induced apoptosis, although it is now known to also play contradictory roles as both a key tumour suppressor and potent oncogene. Because of this pleotropic functionality, targeting JNK directly is unlikely to ever yield successful translation to the clinic. However, we now show that these distinct functions of JNK emerge from two subcellular-specific JNK signalling network states that can exist simultaneously within breast cancer cells, with opposing functional and prognostic roles. By utilising a novel protein-protein interaction based proteomics technique, and high content imaging with a JNK biosensor, we have specifically dissected the signalling complexes that regulate the subcellular activation of JNK in breast cancer. Through this analysis, we now demonstrate that targeting the subcellular activity of JNK represents a viable strategy for specifically inhibiting the oncogenic function of JNK , without impairing its key role as a tumour suppressor.