Exploring the intracellular mechanisms associated with JNK signalling in liver cancers

The JNK protein kinases are master regulators of diverse physiological processes of the cell, including apoptosis, survival, differentiation, proliferation, morphogenesis and inflammatory responses. As such, the JNK signalling pathway acts as a central mechanism imperative for maintaining cell homeostasis and relaying key messages to downstream effectors. However, it has become increasingly clear that the persistent activation of JNK proteins can be non-beneficial, aiding the development and progression of cancers. The dichotomy of JNK signalling is stated clearly within the molecular characterisation of liver cancers, where distinct JNK isoforms act to either suppress or activate various cancer-driving mechanisms. With the aid of a wide range of in vitro and cell-based experimental techniques, in this study I outline the novel interaction of JNK proteins with the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1. Multiple studies have highlighted PIN1 to contribute to the aberrant behaviours of cancer through its unique peptidyl-prolyl cis-trans isomerase (PPIase) activity. As the only known isomerase to recognize and act on phosphorylated Serine/Threonine-Proline motifs, PIN1’s oncogenic potential is substantiated through the diverse range of key protein group targets that incorporate these binding residues. In this study I detail a mechanistic understanding of JNK’s interaction and phosphorylation of PIN1 in cancer, describing the outcome on the stability of PIN1’s protein expression. I then describe the effect of this persistent JNK activity on PIN1’s biological function within cancer, uncovering novel mechanisms for cancer proliferation and enhanced metabolic functions. Given the widely studied aberrant JNK and PIN1 mechanisms within a variety of tissue-specific cancers to date, these findings advance our understanding of oncogenic JNK signalling pathways and are beneficial for targeting of therapeutical intervention.