NUAK Kinases in the Hippo Pathway.

AMP-activated protein kinase (AMPK)-related kinases, especially NUAK1 and NUAK2, have emerged as crucial modulators of Hippo signaling, linking cellular stress, mechanical tension, and metabolic cues to cell growth and survival. By transmitting these signals to the Hippo cascade, either by directly inhibiting large tumor suppressor 1 and 2 (LATS1/2) or by driving cytoskeletal remodeling, NUAKs effectively keep Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in an active state. Excessive expression or activity of NUAKs can dysregulate the Hippo pathway to drive disease, promoting oncogenesis, fibrosis, and contributing to other disorders. Thus, NUAK1 and NUAK2 are attractive, druggable therapeutic targets. Accordingly, small-molecule NUAK inhibitors are in development, several of which have been shown to reactivate Hippo signaling, restore YAP/TAZ cytoplasmic retention, and suppress aberrant cancer cell proliferation and fibrosis. Future work aimed at exploring NUAK regulation and function will not only provide new molecular insights in their mode of action but will also help guide the development of inhibitors that can restore Hippo pathway activity in diverse disease contexts.