Homeodomain-interacting protein kinase regulates Yorkie activity to promote Drosophila tissue growth

The Hippo (Hpo) tumour suppressor pathway regulates tissue size by inhibiting cell proliferation and promoting apoptosis. The core components of the pathway, Hpo, Salvador, Warts (Wts) and Mob-as-tumor-suppressor (Mats), form a kinase cascade to inhibit the activity of the transcriptional regulator Yorkie (Yki). Homeodomain-interacting protein kinases (Hipks) are a family of conserved serine/threonine kinases that regulate various transcriptional factors to control developmental processes including proliferation, differentiation and apoptosis. Hipk can induce tissue overgrowth in Drosophila. Genetic interaction studies reveal that Hipk is required to promote Yki activity, overriding the negative regulation induced by the Hpo kinase cascade. Hipk neither affects Yki stability nor its subcellular localization. Moreover, hipk knockdown suppresses the overgrowth and target gene expression caused by hyperactive Yki. Hipk interacts with and phosphorylates Yki and in vivo analyses show that Hipk’s regulation of Yki is kinase-dependent. To the best of our knowledge, this is the first kinase identified to positively regulate Yki.