Phosphoinositides, which are generated by the phosphorylation of phosphatidylinositol, have important signalling roles in cell proliferation and growth, as well as in diseases including cancer. Phosphatidylinositol 5-monophosphate (PI5P) — which is converted by type II phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) to phosphatidylinositol 4,5-bisphosphate (PIP2, a component of cellular membranes) — is present in cells in low abundance and its role is poorly characterized. Palamiuc et al. have now uncovered a link between PI5P, PI5P4Ks and the Hippo pathway, whereby PI5P reinforces the inhibition of YAP, the effector of the Hippo pathway, thus preventing the activation of cell proliferation- and cancer-associated genes.

As PI5P4Ks convert PI5P to PIP2, the authors went on to analyse the effects of a higher PI5P/PIP2 ratio following Hippo activation and PI5P4K inhibition. Hippo pathway activation in mouse embryonic fibroblasts lacking PI5P4Ks led to an increase in the phosphorylation of MOB1 and activity of the MOB1–LATS complex, indicating that PI5P4Ks inhibit MOB1 phosphorylation and activation of MOB1–LATS. Computational modelling predicts that PI5P can interact with MOB1 and that PI5P binds more tightly to the interface between MOB1 and LATS than PIP2, stabilizing MOB1–LATS and increasing its activity.