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The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis

Nature Cell Biology volume 8, pages 27–36 (2006)Cite this article

Abstract

Merlin, the protein product of the Neurofibromatosis type-2 gene, acts as a tumour suppressor in mice and humans. Merlin is an adaptor protein with a FERM domain and it is thought to transduce a growth-regulatory signal. However, the pathway through which Merlin acts as a tumour suppressor is poorly understood. Merlin, and its function as a negative regulator of growth, is conserved in Drosophila, where it functions with Expanded, a related FERM domain protein. Here, we show that Drosophila Merlin and Expanded are components of the Hippo signalling pathway, an emerging tumour-suppressor pathway. We find that Merlin and Expanded, similar to other components of the Hippo pathway, are required for proliferation arrest and apoptosis in developing imaginal discs. Our genetic and biochemical data place Merlin and Expanded upstream of Hippo and identify a pathway through which they act as tumour-suppressor genes.

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Figure 1: merlin and expanded regulate tissue size.
Figure 2: merlin and expanded regulate cell-cycle arrest and the expression of Cyclin E.
Figure 3: merlin and expanded are required for developmentally induced apoptosis and regulate DIAP1 expression.
Figure 4: Expanded acts genetically upstream of Hippo.
Figure 5: Merlin and Expanded act upstream of Hippo and Warts.
Figure 6: Merlin and Expanded regulate Warts phosphorylation and activity.
Figure 7: Hippo signalling regulates Merlin and Expanded expression and ectopic Hippo is sufficient to rescue expanded mutant phenotypes.
Figure 8: Model of the Hpo signalling pathway.

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Acknowledgements

We thank R.G. Fehon, A. Laughon, M. Mlodzik, B. Hay, D. Pan, P. Bryant, the Bloomington Drosophila Stock Center and the Developmental Studies Hybridoma Bank (University of Iowa) for fly stocks, antibodies and plasmids. We thank K.K. Norga for his help with the isolation of new ex alleles. We thank K.Dunner for technical help with the scanning electron microscopy analysis, which were performed, along with DNA sequencing, at the M. D. Anderson core facilities supported by a National Cancer Institute Cancer Center support grant. We also thank L. McCord for her help with artwork. Special thanks to M. Acar for his invaluable advice and help with the cell-culture experiments. We thank the members of the X. Chen laboratory for their help with antibody production. We thank R. Behringer, H.J. Bellen, A. Bergmann, K.-W. Choi, V. Dion, N. Giagtzoglou, P.R. Hiesinger, G. Lozano, G. Mardon, R. Johnson, J. Kunz and members of the Halder Lab for discussions. This work was supported by a National Institutes of Health grant to G.H, The Odyssey Fellowship and The Theodore N. Law Award for Scientific Achievement to M.K.S., and a BRASS Scholarship to E.H. H.J.N. is supported by HHMI and by a NIH Medical Genetics Research Fellowship Program grant.

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Authors and Affiliations

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

    Fisun Hamaratoglu, Eric Hyun & Georg Halder

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

    Fisun Hamaratoglu, Maria Willecke, Madhuri Kango-Singh, Riitta Nolo, Eric Hyun, Chunyao Tao & Georg Halder

  3. Interfakultäres Institut für Zellbiologie, Abt. Genetik der Tiere, Universität Tübingen, Tübingen, 72076, Germany

    Maria Willecke

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, USA

    Hamed Jafar-Nejad

  5. Program in Genes and Development, University of Texas M. D. Anderson Cancer Center, Houston, 77030, TX, USA

    Georg Halder

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Correspondence to Georg Halder.

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Hamaratoglu, F., Willecke, M., Kango-Singh, M. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 8, 27–36 (2006). https://doi.org/10.1038/ncb1339

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