Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development.

The proto-oncoprotein c-Jun is a component of the AP-1 transcription factor, the activity of which is augmented in many tumour types. An important mechanism in the stimulation of AP-1 function is amino-terminal phosphorylation of c-Jun by the c-Jun N-terminal kinases (JNKs). Phosphorylated c-Jun is biologically more active, partially because it acquires the ability to interact with binding partners. Here we show that phosphorylated c-Jun interacts with the HMG-box transcription factor TCF4 to form a ternary complex containing c-Jun, TCF4 and beta-catenin. Chromatin immunoprecipitation assays revealed JNK-dependent c-Jun-TCF4 interaction on the c-jun promoter, and c-Jun and TCF4 cooperatively activated the c-jun promoter in reporter assays in a beta-catenin-dependent manner. In the Apc(Min) mouse model of intestinal cancer, genetic abrogation of c-Jun N-terminal phosphorylation or gut-specific conditional c-jun inactivation reduced tumour number and size and prolonged lifespan. Therefore, the phosphorylation-dependent interaction between c-Jun and TCF4 regulates intestinal tumorigenesis by integrating JNK and APC/beta-catenin, two distinct pathways activated by WNT signalling.