The activity of the transcription factor c-JUN is increased in several human cancers. In their Nature paper, Axel Behrens and colleagues now show that c-JUN is part of a transcriptional complex that is central to the development of colorectal cancer.

Loss of the adenomatous polyposis coli gene (APC) predisposes individuals to an increased risk of developing colorectal cancer. APC binds to axin and the glycogen synthase kinase GSK3β, and this complex phosphorylates the transcription regulator β-catenin, marking it for ubiquitylation and degradation. Only when WNT binds to its receptor, Frizzled, is this complex disrupted, allowing β-catenin to accumulate in the nucleus. Here it interacts with members of the transcription factor family T-cell factor/lymphoid enhancing factor (TCF/LEF). WNT signalling can also affect other pathways including activation of the c-JUN N-terminal kinases (JNK s) that activate c-JUN by phosphorylating its N-terminus. The authors had previously identified factors that bind specifically to phosphorylated c-JUN and one of these was TCF4. As TCF4 can also interact with β-catenin, the authors investigated the interaction of TCF4 with both β-catenin and c-JUN. They found that the interaction of TCF4 with c-JUN is dependent on the phosphorylation of two N-terminal serines (Ser63 and Ser73) in c-JUN, and that TCF4 can bind both β-catenin and c-JUN simultaneously.