Hippo pathway regulates caveolae expression and mediates flow response via caveolae

The Hippo pathway is a key regulator of cell survival, proliferation and tissue homeostasis. In addition, it is vital for development and regeneration. The activity of the Hippo pathway depends on intra- and extra-cellular signals and is tightly regulated by diffusible chemicals as well as mechanical stimuli. The pathway comprises of a kinase cascade that controls the activity of YAP and TAZ, homologous transcriptional co-activators. Despite its central role in most cells the overall regulation of the Hippo pathway, especially originating from the plasma membrane, is not yet fully understood. Caveolae are 50-100 nm bulb-shaped plasma membrane invaginations that function in endocytosis, protection from mechanical stress and in cell signalling. Hence, the aim was to identify if caveolae and the Hippo pathway are functionally linked. This thesis reveals that the central caveolar components CAVEOLIN1 and CAVIN1 depend on YAP/TAZ. CAVEOLIN1 and CAVIN1 are direct YAP-TEAD target genes and YAP/TAZ are essential for the expression of caveolar components in mammalian cells and in zebrafish. Moreover, CAVEOLIN1 dictates YAP/TAZ subcellular localisation and inhibits their activity. Notably, in cells with diminished levels of caveolae, YAP/TAZ are hyperactive (nuclear), which led to increased induction of gene transcription. Finally, the activation of YAP/TAZ by shear stress is partly dependent on caveolae. These data link caveolae to Hippo pathway signalling in the context of cellular responses to mechanical stimuli and suggest feedback regulation between the Hippo pathway co-transcriptional activators YAP/TAZ and essential caveolae components.