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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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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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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DOI: https://doi.org/10.1038/ncb1339
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