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Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway

Nature Cell Biology volume 5, pages 914–920 (2003)Cite this article

Abstract

Proliferation and apoptosis must be precisely regulated to form organs with appropriate cell numbers and to avoid tumour growth1,2. Here we show that Hippo (Hpo), the Drosophila homologue of the mammalian Ste20-like kinases3, MST1/2, promotes proper termination of cell proliferation and stimulates apoptosis during development. hpo mutant tissues are larger than normal because mutant cells continue to proliferate beyond normal tissue size and are resistant to apoptotic stimuli that usually eliminate extra cells. Hpo negatively regulates expression of Cyclin E to restrict cell proliferation, downregulates the Drosophila inhibitor of apoptosis protein DIAP1, and induces the proapoptotic gene head involution defective (hid) to promote apoptosis. The mutant phenotypes of hpo are similar to those of warts (wts), which encodes a serine/threonine kinase of the myotonic dystrophy protein kinase family4,5, and salvador (sav), which encodes a WW domain protein that binds to Wts6,7. We find that Sav binds to a regulatory domain of Hpo that is essential for its function, indicating that Hpo acts together with Sav and Wts in a signalling module that coordinately regulates cell proliferation and apoptosis.

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Figure 1: hippo regulates tissue size, cell-cycle arrest and expression of Cyclin E.
Figure 2: hippo is required for apoptosis in eye development and regulates DIAP1.
Figure 3: Hpo is a Ste20 family kinase that interacts with Sav and induces apoptosis.
Figure 4: Hid and Wts are required for Hippo action.

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Acknowledgements

We thank K. Basler, H. J. Bellen, A. Bergmann, P. Bryant, K.-W. Choi, B. Dickson, B. Edgar, B. Hay, G. Mardon, M. Miura, A. Singh, the Bloomington Drosophila Stock Center, and the Developmental Studies Hybridoma Bank for fly stocks and antibodies; H. Jafar-Nejad for technical advice with the yeast-two-hybrid screen; G. Zhai for help with SNP detection by HPLC; P. R. Hiesinger for help with pupal stainings; J. Zhang for help with microinjections; K. Dunner for help with SEM, which along with DNA sequencing was done at M. D. Anderson core facilities, which is supported by a grant from the National Cancer Institute (CA16672); L. McCord for help with artwork; and H. J. Bellen, A. Bergmann, B. Frankfort, P. R. Hiesinger, R. Johnson, J. Kunz, S. Markus, K. Pappu, A. Singh and G. Zhai for discussion and comments on the manuscript. This publication was made possible by grants from the NIEHS (T32 ES07332) and the NICHD (HD07325) to R.U., and an NIH grant (GM067997), a Pharmacia Research Grant and a Basil O'Connor Award (FY01-497) to G.H.

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Author notes

  1. Ryan S. Udan and Madhuri Kango-Singh: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Developmental Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Ryan S. Udan & Georg Halder

  2. Department of Biochemistry and Molecular Biology, M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Ryan S. Udan, Madhuri Kango-Singh, Riitta Nolo, Chunyao Tao & Georg Halder

  3. The Genes and Development Graduate Program, The University of Texas Graduate School of Biomedical Sciences, M. D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Georg Halder

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Correspondence to Georg Halder.

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Udan, R., Kango-Singh, M., Nolo, R. et al. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol 5, 914–920 (2003). https://doi.org/10.1038/ncb1050

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