The Hippo pathway in disease and therapy: cancer and beyond

Abstract

The Hippo tumour suppressor pathway co-ordinates cell proliferation, cell death and cell differentiation to regulate tissue growth control. In mammals, a conserved core Hippo signalling module receives signal inputs on different levels to ensure the proper regulation of YAP/TAZ activities as transcriptional co-activators. While the core module members MST1/2, Salvador, LATS1/2 and MOB1 have been attributed tumour suppressive functions, YAP/TAZ have been mainly described to have oncogenic roles, although some reports provided evidence supporting growth suppressive roles of YAP/TAZ in certain cancer settings. Intriguingly, mammalian Hippo signalling is also implicated in non-cancer diseases and plays a role in tissue regeneration following injury. Cumulatively, these findings indicate that the pharmacological inhibition or activation of the Hippo pathway could be desirable depending on the disease context. In this review, we first summarise the functions of the mammalian Hippo pathway in tumour formation, and then discuss non-cancer diseases involving Hippo signalling core components with a specific focus on our current understanding of the non-cancer roles of MST1/2 and YAP/TAZ. In addition, the pros and cons of possible pharmacological interventions with Hippo signalling will be reviewed, with particular emphasis on anti-cancer drug development and regenerative medicine.

Keywords: Cancer; Hippo signalling cascade; LATS; MOB1; MST; Protein kinases; Protein-protein interactions; Scaffolding proteins; Therapy; Tissue repair.

Figure 1

The Hippo signalling core cassette in mammals. In response to upstream signals (coming from GPCRs and other plasma membrane associated factors), MST1/2 are activated by phosphorylation. Phosphorylated MST1/2 in complex with the scaffolding protein SAV then activates LATS1/2 kinases by phosphorylation. Activated LATS1/2, associated with their co-activator MOB1, hyperphosphorylate YAP/TAZ on different sites. These YAP/TAZ phosphorylation events create a 14-3-3 binding site that causes the cytoplasmic retention of YAP/TAZ (mediated by Ser127 phosphorylation of YAP) and a separate phospho-degron that mediates the proteasomal degradation of YAP/TAZ (mediated by Ser381 phosphorylation of YAP). When the Hippo pathway is inactive, YAP/TAZ are not phosphorylated by LATS1/2 allowing the transcriptional co-activators YAP/TAZ to accumulate in the nucleus which can result in the transcription of specific target genes involved in cell cycle, apoptosis and differentiation control. Of note, the MST1/2-LATS1/2-YAP/TAZ axis can also be influenced by additional factors (depicted as X) on each individual signalling level.