The Salvador-Warts-Hippo (SWH) pathway is a complex signaling network that controls both developmental and regenerative tissue growth. Using a genetic screen in Drosophila melanogaster, we identified the sterile 20-like kinase, Tao-1, as an SWH pathway member. Tao-1 controls various biological phenomena, including microtubule dynamics, animal behavior, and brain development. Here we describe a role for Tao-1 as a regulator of epithelial tissue growth that modulates activity of the core SWH pathway kinase cassette. Tao-1 functions together with Hippo to activate Warts-mediated repression of Yorkie. Tao-1's ability to control SWH pathway activity is evolutionarily conserved because human TAO1 can suppress activity of the Yorkie ortholog, YAP. Human TAO1 controls SWH pathway activity by phosphorylating, and activating, the Hippo ortholog, MST2. Given that SWH pathway activity is subverted in many human cancers, our findings identify human TAO kinases as potential tumor suppressor genes.

A key question in developmental neurobiology is how neural stem cells regulate their proliferative potential and cellular diversity and thus specify the overall size of the brain. Drosophila melanogaster neural stem cells (neuroblasts) are known to regulate their ability to self-renew by asymmetric cell division and produce different types of neurons and glia through sequential expression of temporal transcription factors [1]. Here, we show that the conserved Hippo pathway, a key regulator of epithelial organ size [2-4], restricts neuroblast proliferative potential and neuronal cell number to regulate brain size. The inhibition of Hippo pathway activity via depletion of the core kinases Tao-1, Hippo, or Warts regulates several key characteristics of neuroblasts during postembryonic neurogenesis. The Hippo pathway is required to maintain timely entry and exit from neurogenesis by regulating both neuroblast reactivation from quiescence and the time at which neuroblasts undergo terminal differentiation. Further, it restricts neuroblast cell-cycle speed, specifies cell size, and alters the proportion of neuron types generated during postembryonic neurogenesis. Collectively, deregulation of Hippo signaling in neuroblasts causes a substantial increase in overall brain size. We show that these effects are mediated via the key downstream transcription co-activator Yorkie and that, indeed, Yorkie overexpression in neuroblasts is sufficient to cause brain overgrowth. These studies reveal a novel mechanism that controls stem cell proliferative potential during postembryonic neurogenesis to regulate brain size.

The Salvador-Warts-Hippo (SWH) pathway is an evolutionarily conserved regulator of tissue growth that is deregulated in human cancer. Upstream SWH pathway components convey signals from neighboring cells via a core kinase cassette to the transcription coactivator Yorkie (Yki). Yki controls tissue growth by modulating activity of transcription factors including Scalloped (Sd). To date, five SWH pathway kinases have been identified, but large-scale phosphoproteome studies suggest that unidentified SWH pathway kinases exist. To identify such kinases, we performed an RNA interference screen and isolated homeodomain-interacting protein kinase (Hipk). Unlike previously identified SWH pathway kinases, Hipk is unique in its ability to promote, rather than repress, Yki activity and does so in parallel to the Yki-repressive kinase, Warts (Wts). Hipk is required for basal Yki activity and is likely to regulate Yki function by promoting its accumulation in the nucleus. Like many SWH pathway proteins, Hipk's function is evolutionarily conserved as its closest human homolog, HIPK2, promotes activity of the Yki ortholog YAP in a kinase-dependent fashion. Further, HIPK2 promotes YAP abundance, suggesting that the mechanism by which HIPK2 regulates YAP has diverged in mammals.