Sekar, A.; Rizzo, A.; Sins, E.; Fulford, A. D.; Ribeiro, P. S.

Hippo signalling is an evolutionarily conserved pathway that regulates tissue growth. The FERM domain protein Expanded plays a crucial role in integrating polarity cues to activate the Hippo pathway. Previous work has shown that the apicobasal polarity protein Crumbs can limit Hippo activity by promoting the phosphorylation and degradation of Expanded. Here, we provide evidence that PP2AWrd can counteract the effects of Crumbs, by dephosphorylating and stabilising Expanded. Indeed, we demonstrate that the PP2AWrd holoenzyme can increase Hippo signalling activity, in contrast to the previously established Hippo pathway inhibitory role of the PP2ACka-containing STRIPAK complex. We also uncover a role for PP2AWrd and PP2ATws in the regulation of Expanded proteostasis. Remarkably, the upstream Hippo regulator, Kibra interacts with PP2AWrd and prevents Expanded degradation. However, Kibra is unable to antagonise Crumbs-mediated Expanded regulation, in agreement with the previously established role of Crumbs in inhibiting Kibra function. Overall, our work characterises a novel Hippo-activating role for PP2A in the stabilisation of Expanded and provides new insights into how PP2A tightly controls Hippo activity in response to polarity stimuli.