The specification of tissue size during development involves the coordinated action of many signalling pathways responding to organ-intrinsic signals, such as morphogen gradients, and systemic cues, such as nutrient status. The conserved Hippo (Hpo) pathway, which promotes both cell-cycle exit and apoptosis, is a major determinant of size control. The pathway core is a kinase cassette, comprising the kinases Hpo and Warts (Wts) and the scaffold proteins Salvador (Sav) and Mats, which inactivates the pro-growth transcriptional co-activator Yorkie (Yki). We performed a split-TEV-based genome-wide RNAi screen for modulators of Hpo signalling. We characterize the Drosophila salt-inducible kinases (Sik2 and Sik3) as negative regulators of Hpo signalling. Activated Sik kinases increase Yki target expression and promote tissue overgrowth through phosphorylation of Sav at Ser 413. As Sik kinases have been implicated in nutrient sensing, this suggests a link between the Hpo pathway and systemic growth control.
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We thank A. Kerai for help with re-screening candidates; T. Gilbank, S. Maloney and F. Earl for maintaining flies; L. Muthusamy for sequencing and helping with plating RNAi libraries; the Vienna Drosophila RNAi Centre for fly stocks; and O. Shaham and B. Thompson for comments on the manuscript. We are very grateful to P. Gaspar for help with fly genetics; F. Josue and P. Langton for advice; and A. Teleman and A. Celik for sharing reagents and exchanging unpublished data before publication. We thank K-A. Nave (Göttingen) for ongoing support. M.C.W. and M.J.R. acknowledge the support by the Bundesministerium für Wirtschaft und Forschung (grants 03EFT6N1 and 16V0008). M.C.W. was supported by an EMBO Long-Term Fellowship. The Tapon laboratory is supported by Cancer Research UK.
The authors declare no competing financial interests.
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Wehr, M., Holder, M., Gailite, I. et al. Salt-inducible kinases regulate growth through the Hippo signalling pathway in Drosophila. Nat Cell Biol 15, 61–71 (2013). https://doi.org/10.1038/ncb2658
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