The c-Jun N-terminal Kinase (JNK) is a member of the mitogen activated protein kinase (MAPK) family and is activated by a range of different stimuli; including growth factors, cytokines, matrix interactions and cell stress. Once activated, JNK can phosphorylate a wide array of substrates and thereby control distinct and often opposing cell behaviour such as apoptosis, differentiation, cell growth, survival, invasion and drug resistance.

This broad sensitivity and pleiotropic functionality of JNK signalling has led to various characterisations of JNK as either a central drug response pathway, an oncogene, or a tumour suppressor. Seminal studies within this field have adopted systems level approaches in order to dissect this multivariate capacity of JNK, and demonstrated that the downstream function of JNK is determined by the network state in which JNK is active, not solely by its activation level. Further to this, we now show that two distinct JNK network states can exist simultaneously within breast cancer cells, with opposing functional and prognostic roles.

These two network states are spatially separated into an oncogenic, cytosolic JNK pool and a tumour suppressing, nuclear JNK pool. Using JNK biosensors and high content imaging we have dissected the upstream kinases regulating these networks, and demonstrated that this localisation switch can be mediated by increased stiffness of the extracellular matrix, which promotes cytoplasmic JNK activation while repressing nuclear JNK activation. Through further characterisation of these opposing network states we aim to develop strategies for targeting the oncogenic function of JNK without impairing its tumour suppressor or apoptotic function.