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Abstract IA10: Inhibition of the Hippo pathway by AMPK-family kinases

Inactivation of the Hippo pathway is a common feature in numerous cancers, yet mutations in pathway components are relatively rare. To uncover novel Hippo pathway regulators, we conducted multidimensional high-throughput screens. These efforts uncovered two AMPK family kinases, MARK4 and NUAK2, as negative regulators of the Hippo pathway. MARK kinases, including MARK3 and MARK4, phosphorylate both SAV1 and MST1/2 and inhibit MST1/2-dependent activation of LATS. Moreover, we showed that DLG5 acts as a scaffold to promote MARK-mediated phosphorylation of MST. In contrast to MARKs, NUAK2 interacts with and phosphorylates LATS. Interestingly, NUAK2 is induced by YAP/TAZ in cooperation with AP-1 and this is required for robust YAP/TAZ signaling. Inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. In human patient samples, NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. Thus, we identified a positive feed-forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ. Citation Format: Liliana Attisano. Inhibition of the Hippo pathway by AMPK-family kinases [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA10.