The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila

Abstract

Tissue growth during animal development is tightly controlled so that the organism can develop harmoniously1. The salvador (sav) gene, which encodes a scaffold protein, has been shown to restrict cell number by coordinating cell-cycle exit and apoptosis during Drosophila development2,3. Here we identify Hippo (Hpo), the Drosophila orthologue of the mammalian MST1 and MST2 serine/threonine kinases, as a partner of Sav. Loss of hpo function leads to sav-like phenotypes, whereas gain of hpo function results in the opposite phenotype. Whereas Sav and Hpo normally restrict cellular quantities of the Drosophila inhibitor of apoptosis protein DIAP1, overexpression of Hpo destabilizes DIAP1 in cell culture. We show that DIAP1 is phosphorylated in a Hpo-dependent manner in S2 cells and that Hpo can phosphorylate DIAP1 in vitro. Thus, Hpo may promote apoptosis by reducing cellular amounts of DIAP1. In addition, we show that Sav is an unstable protein that is stabilized by Hpo. We propose that Hpo and Sav function together to restrict tissue growth in vivo.

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Figure 1: Salvador and Wts interact with Hpo.
Figure 2: RNAi-mediated hpo LOF induces organ overgrowth.
Figure 3: hpo downregulation prevents cell-cycle exit and apoptosis in the eye imaginal disc.
Figure 4: Hpo induces DIAP1 and Sav phosphorylation, and modulates their stability.

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Acknowledgements

We thank I. Hariharan, S. Noselli, S. Schelble, H. Steller and K. White for fly stocks; R. Finley, C Ghiglione, E. Giordano, R. Hays, A.-O. Hueber, A. Plessis, J. Pouysségur's laboratory, L. Ruel and K. White for plasmids and reagents; R. Arkowitz and his laboratory for help with the yeast two-hybrid assay; R. Arkowitz, B. Hay, and H. Richardson for antibodies; I. Hariharan, K. Harvey, C. Pfleger and G. Halder for discussing data before publication; M.-T. Ravier for technical assistance; and members of the Léopold, Thérond and Noselli laboratories for discussions. This work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer, and the Association pour la Sclérose Tubéreuse de Bourneville.

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Correspondence to Nicolas Tapon.

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Pantalacci, S., Tapon, N. & Léopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5, 921–927 (2003) doi:10.1038/ncb1051

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