Shaggy regulates tissue growth through Hippo pathway in Drosophila.

The evolutionarily conserved Hippo pathway coordinates cell proliferation, differentiation and apoptosis to regulate organ growth and tumorigenesis. Hippo signaling activity is tightly controlled by various upstream signals including growth factors and cell polarity, but the full extent to which the pathway is regulated during development remains to be resolved. Here, we report the identification of Shaggy, the homolog of mammalian Gsk3β, as a novel regulator of the Hippo pathway in Drosophila. Our results show that Shaggy promotes the expression of Hippo target genes in a manner that is dependent on its kinase activity. Loss of Shaggy leads to Yorkie inhibition and downregulation of Hippo pathway target genes. Mechanistically, Shaggy acts upstream of the Hippo pathway and negatively regulates the abundance of the FERM domain containing adaptor protein Expanded. Our results reveal that Shaggy is functionally required for Crumbs/Slmb-mediated downregulation of Expanded in vivo, providing a potential molecular link between cellular architecture and the Hippo signaling pathway.