Time-lapse imaging of Clover-YAP WT (first movie) and 5SA (second movie) in MDA-MB231 cells. Localization of Clover-YAP WT (wild type) and 5SA (mutant at all five LATS targeting sites) was monitored before and after addition of NUAK2 specific inhibitor, WZ4003. Note that the nuclear signal is gradually lost after addition of WZ4003 in cells expressing YAP-WT but not affected in YAP-5SA. Images were captured every 10 min for 2 hours. The scale and timestamp are indicated in the movie.

In most solid tumors, inactivation of the Hippo pathway, occurring through poorly understood mechanism, enables activation of the YAP/TAZ transcriptional program which promotes tumor initiation, progression and metastasis. In a recent publication in Nature Communication, Liliana Attisano’s lab at the Donnelly Center and her collaborators at Lunenfeld-Tanenbaum Research Institute and the Hospital for Sick Children revealed a positive feed forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumour promoting activities of YAP/TAZ.

To uncover cancer-relevant activators of YAP/TAZ, Attisano’s group performed a high-throughput human kinome RNAi screen and identified NUAK2, a member of the AMPK-related family of serine/threonine kinases, as a positive regulator of YAP/TAZ. Mechanistically, NUAK2 is shown to modulate Hippo pathway by phosphorylating a key pathway component, LATS, thereby inhibiting LATS mediated phosphorylation of YAP both in vitro and in intact cells. Moreover, NUAK2 is shown to act in a positive feed forward loop in which YAP/TAZ induce expression of NUAK2 and NUAK2 activation in turn serves to directly inhibit the Hippo pathway via LATS, thus driving robust YAP/TAZ signaling. Notably, pharmacological inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. Furthermore, it was shown that NUAK2 expression is elevated in aggressive, high grade bladder cancer patient samples and strongly correlates with a YAP/TAZ gene signature.  Altogether, the findings highlight the anti-cancer potential of NUAK2 that could be used as therapeutic target to counteract the oncogenic functions of YAP/TAZ.