Key Points
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Studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelia. Although this pathway is currently poorly characterized in mammals, several components of the Hippo pathway appear to function as tumour suppressors.
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The protein Fat, originally discovered in D. melanogaster as the founding member of a subfamily of genes called protocadherins, has been newly identified as an upstream regulator of the Hippo pathway. The data suggest that Fat increases Hippo activity by two mechanisms: it modulates Hippo activity through phosphorylation and stabilizes the Warts protein (a central kinase of the Hippo signal transduction pathway).
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Two recent reports have identified a new transcriptional target downstream of the Hippo pathway in D. melanogaster that can promote tissue growth and inhibit apoptosis: the microRNA bantam. However, it remains unclear how bantam promotes cell proliferation and whether the mechanism(s) is conserved in mammals.
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In flies and mammals, Hippo signalling promotes apoptosis in response to irradiation. Recent work in D. melanogaster suggests that p53 is responsible for the activation of Hippo following irradiation, and that members of the Ras association family can temper this response.
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Loss of Hippo signalling allows cells in the developing fly to outcompete and eliminate neighbouring wild-type cells. This phenomenon is known as supercompetition. The mechanism(s) that enables Hippo-mutant cells to act as 'supercompetitors' remains unclear.
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Two unresolved questions pertaining to the Hippo pathway are: do extracellular ligands regulate Hippo activity by binding to Fat? And does the supercompetition phenotype of Hippo mutants contribute to mammalian tumorigenesis?
Abstract
How cell numbers are controlled during organ development is a problem that is still in need of answers. Recent studies in Drosophila melanogaster have delineated a novel signalling pathway, the Hippo pathway, which has an important role in restraining cell proliferation and promoting apoptosis in differentiating epithelial cells. Much like cancer cells, cells that contain mutations for components of the Hippo pathway proliferate inappropriately and have a competitive edge in genetically mosaic tissues. Although poorly characterized in mammals, several components of the Hippo pathway seem to be tumour suppressors in humans.
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References
Xu, T. & Rubin, G. M. Analysis of genetic mosaics in developing and adult Drosophila tissues. Development 117, 1223–1237 (1993).
Potter, C. J., Turenchalk, G. S. & Xu, T. Drosophila in cancer research. An expanding role. Trends Genet. 16, 33–39 (2000).
McClatchey, A. I. & Giovannini, M. Membrane organization and tumorigenesis — the NF2 tumor suppressor, Merlin. Genes Dev. 19, 2265–2277 (2005).
Overholtzer, M. et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc. Natl Acad. Sci. USA 103, 12405–12410 (2006).
Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006).
Edgar, B. A. From cell structure to transcription: Hippo forges a new path. Cell 124, 267–273 (2006).
Pan, D. Hippo signaling in organ size control. Genes Dev. 21, 886–897 (2007).
Harvey, K. & Tapon, N. The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network. Nature Rev. Cancer 7, 182–191 (2007).
Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).
Xu, T. A., Wang, W. Y., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics — the Drosophila lats gene encodes a putative protein-kinase. Development 121, 1053–1063 (1995).
Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457–467 (2003).
Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).
Pantalacci, S., Tapon, N. & Leopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nature Cell Biol. 5, 921–927 (2003).
Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).
Udan, R. S., Kango-Singh, M., Nolo, R., Tao, C. & Halder, G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nature Cell Biol. 5, 914–920 (2003).
Wu, S., Huang, J., Dong, J. & Pan, D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell 114, 445–456 (2003).
Lai, Z. C. et al. Control of cell proliferation and apoptosis by mob as tumor suppressor, mats. Cell 120, 675–685 (2005).
Wei, X., Shimizu, T. & Lai, Z. C. Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila. EMBO J. 26, 1772–1781 (2007).
Chan, E. H. et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene 24, 2076–2086 (2005).
Hergovich, A., Schmitz, D. & Hemmings, B. A. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem. Biophys. Res. Commun. 345, 50–58 (2006).
Callus, B. A., Verhagen, A. M. & Vaux, D. L. Association of mammalian sterile twenty kinases, Mst1 and Mst2, with hSalvador via C-terminal coiled-coil domains, leads to its stabilization and phosphorylation. FEBS J. 273, 4264–4276 (2006).
Huang, J., Wu, S., Barrera, J., Matthews, K. & Pan, D. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila homolog of YAP. Cell 122, 421–434 (2005).
Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol. Cell 18, 447–459 (2005).
Howell, M., Borchers, C. & Milgram, S. L. Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co-activation of Bax transcription. J. Biol. Chem. 279, 26300–26306 (2004).
Zaidi, S. K. et al. Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J. 23, 790–799 (2004).
Komuro, A., Nagai, M., Navin, N. E. & Sudol, M. WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J. Biol. Chem. 278, 33334–33341 (2003).
Ferrigno, O. et al. Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling. Oncogene 21, 4879–4884 (2002).
Espanel, X. & Sudol, M. Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J. Biol. Chem. 276, 14514–14523 (2001).
Yagi, R., Chen, L. F., Shigesada, K., Murakami, Y. & Ito, Y. A WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J. 18, 2551–2562 (1999).
Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell Death Differ. 14, 743–751 (2007).
Guo, J. et al. Yes-associated protein (YAP65) in relation to Smad7 expression in human pancreatic ductal adenocarcinoma. Int. J. Mol. Med. 17, 761–767 (2006).
Vassilev, A., Kaneko, K. J., Shu, H., Zhao, Y. & DePamphilis, M. L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15, 1229–1241 (2001).
Basu, S., Totty, N. F., Irwin, M. S., Sudol, M. & Downward, J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell 11, 11–23 (2003).
Strano, S. et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164–15173 (2001).
Bretscher, A., Edwards, K. & Fehon, R. G. ERM proteins and merlin: integrators at the cell cortex. Nature Rev. Mol. Cell Biol. 3, 586–599 (2002).
Boedigheimer, M. & Laughon, A. expanded: a gene involved in the control of cell proliferation in imaginal discs. Development 118, 1291–1301 (1993).
Boedigheimer, M. J., Nguyen, K. P. & Bryant, P. J. expanded functions in the apical cell domain to regulate the growth rate of imaginal discs. Dev. Genet. 20, 103–110 (1997).
McCartney, B. M., Kulikauskas, R. M., LaJeunesse, D. R. & Fehon, R. G. The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation. Development 127, 1315–1324 (2000).
Hamaratoglu, F. et al. The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nature Cell Biol. 8, 27–36 (2006).
Pellock, B. J., Buff, E., White, K. & Hariharan, I. K. The Drosophila tumor suppressors Expanded and Merlin differentially regulate cell cycle exit, apoptosis, and Wingless signaling. Dev. Biol. 304, 102–115 (2007).
Okada, T., Lopez-Lago, M. & Giancotti, F. G. Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane. J. Cell Biol. 171, 361–371 (2005).
Shaw, R. J. et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev. Cell 1, 63–72 (2001).
Lallemand, D., Curto, M., Saotome, I., Giovannini, M. & McClatchey, A. I. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 17, 1090–1100 (2003).
McPherson, J. P. et al. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J. 23, 3677–3688 (2004).
Neufeld, T. P., de la Cruz, A. F., Johnston, L. A. & Edgar, B. A. Coordination of growth and cell division in the Drosophila wing. Cell 93, 1183–1193 (1998).
Buttitta, L. A double-assurance mechanism controls cell cycle exit at differentiation in Drosophila. Dev. Cell 12, 631–643 (2007).
Yang, X., Li, D. M., Chen, W. & Xu, T. Human homologue of Drosophila lats, LATS1, negatively regulate growth by inducing G(2)/M arrest or apoptosis. Oncogene 20, 6516–6523 (2001).
Xia, H. et al. LATS1 tumor suppressor regulates G2/M transition and apoptosis. Oncogene 21, 1233–1241 (2002).
Li, Y. et al. Lats2, a putative tumor suppressor, inhibits G1/S transition. Oncogene 22, 4398–4405 (2003).
Lee, K. K., Ohyama, T., Yajima, N., Tsubuki, S. & Yonehara, S. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J. Biol. Chem. 276, 19276–19285 (2001).
Avruch, J., Praskova, M., Ortiz-Vega, S., Liu, M. & Zhang, X. F. Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases. Methods Enzymol. 407, 290–310 (2005).
Praskova, M., Khoklatchev, A., Ortiz-Vega, S. & Avruch, J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem. J. 381, 453–462 (2004).
Guo, C. et al. RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network. Curr. Biol. 17, 700–705 (2007).
Bryant, P. J., Huettner, B., Held, L. I. Jr, Ryerse, J. & Szidonya, J. Mutations at the fat locus interfere with cell proliferation control and epithelial morphogenesis in Drosophila. Dev. Biol. 129, 541–554 (1988).
Mahoney, P. A. et al. The fat tumor suppressor gene in Drosophila encodes a novel member of the cadherin gene superfamily. Cell 67, 853–868 (1991).
Matakatsu, H. & Blair, S. S. Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131, 3785–3794 (2004).
Hong, J. C. et al. Identification of new human cadherin genes using a combination of protein motif search and gene finding methods. J. Mol. Biol. 337, 307–317 (2004).
Ma, D., Yang, C. H., McNeill, H., Simon, M. A. & Axelrod, J. D. Fidelity in planar cell polarity signalling. Nature 421, 543–547 (2003).
Cho, E. & Irvine, K. D. Action of fat, four-jointed, dachsous and dachs in distal-to-proximal wing signaling. Development 131, 4489–4500 (2004).
Jaiswal, M., Agrawal, N. & Sinha, P. Fat and Wingless signaling oppositely regulate epithelial cell–cell adhesion and distal wing development in Drosophila. Development 133, 925–935 (2006).
Strutt, H. & Strutt, D. Long-range coordination of planar polarity in Drosophila. Bioessays 27, 1218–1227 (2005).
Bennett, F. C. & Harvey, K. F. Fat cadherin modulates organ size in Drosophila via the Salvador/Warts/Hippo signaling pathway. Curr. Biol. 16, 2101–2110 (2006).
Cho, E. et al. Delineation of a Fat tumor suppressor pathway. Nature Genet. 38, 1142–1150 (2006).
Silva, E., Tsatskis, Y., Gardano, L., Tapon, N. & McNeill, H. The tumor-suppressor gene fat controls tissue growth upstream of expanded in the hippo signaling pathway. Curr. Biol. 16, 2081–2089 (2006).
Willecke, M. et al. The fat cadherin acts through the hippo tumor-suppressor pathway to regulate tissue size. Curr. Biol. 16, 2090–2100 (2006).
Tyler, D. M. & Baker, N. E. Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev. Biol. 305, 187–201 (2007). References 62–66 all report independent findings that provide a considerable amount of biochemical and genetic data to position the Hippo pathway as the general mediator of Fat signalling in growth control.
Formstecher, E. et al. Protein interaction mapping: a Drosophila case study. Genome Res. 15, 376–384 (2005).
Mao, Y. et al. Dachs: an unconventional myosin that functions downstream of Fat to regulate growth, affinity and gene expression in Drosophila. Development 133, 2539–2551 (2006).
Nolo, R., Morrison, C. M., Tao, C., Zhang, X. & Halder, G. The bantam microRNA is a target of the hippo tumor-suppressor pathway. Curr. Biol. 16, 1895–1904 (2006).
Thompson, B. J. & Cohen, S. M. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Cell 126, 767–774 (2006). References 69 and 70 demonstrate that activation of Yki (normally inhibited by Hippo signalling) leads to the transcriptional induction of bantam , a microRNA that has the ability to promote tissue growth and inhibit apoptosis.
Hipfner, D. R., Weigmann, K. & Cohen, S. M. The bantam gene regulates Drosophila growth. Genetics 161, 1527–1537 (2002).
Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).
Matakatsu, H. & Blair, S. S. Separating the adhesive and signaling functions of the Fat and Dachsous protocadherins. Development 133, 2315–2324 (2006).
Maitra, S., Kulikauskas, R. M., Gavilan, H. & Fehon, R. G. The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr. Biol. 16, 702–709 (2006).
Garoia, F. et al. The tumor suppressor gene fat modulates the EGFR-mediated proliferation control in the imaginal tissues of Drosophila melanogaster. Mech. Dev. 122, 175–187 (2005).
Yang, L. & Baker, N. E. Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye. Dev. Cell 4, 359–369 (2003).
O'Neill, E. & Kolch, W. Taming the Hippo: Raf-1 controls apoptosis by suppressing MST2/Hippo. Cell Cycle 4, 365–367 (2005).
Colombani, J., Polesello, C., Josue, F. & Tapon, N. Dmp53 activates the Hippo pathway to promote cell death in response to DNA damage. Curr. Biol. 16, 1453–1458 (2006).
Polesello, C., Huelsmann, S., Brown, N. H. & Tapon, N. The Drosophila RASSF homolog antagonizes the hippo pathway. Curr. Biol. 16, 2459–2465 (2006).
Morata, G. & Ripoll, P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev. Biol. 42, 211–221 (1975).
Lambertsson, A. The minute genes in Drosophila and their molecular functions. Adv. Genet. 38, 69–134 (1998).
de la Cova, C., Abril, M., Bellosta, P., Gallant, P. & Johnston, L. A. Drosophila myc regulates organ size by inducing cell competition. Cell 117, 107–116 (2004).
Moreno, E. & Basler, K. dMyc transforms cells into super-competitors. Cell 117, 117–129 (2004).
Tyler, D., Li, W., Zhuo, N., Pellock, B. J. & Baker, N. E. Genes affecting cell competition in Drosophila melanogaster. Genetics 175, 643–657 (2006). Shows that mutations in components of the Hippo pathway enable cells to outcompete and eliminate wild-type neighbouring cells. However, the mechanisms that underlie this phenotype remain unclear.
Grewal, S. S., Li, L., Orian, A., Eisenman, R. N. & Edgar, B. A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nature Cell Biol. 7, 295–302 (2005).
Oskarsson, T. & Trumpp, A. The Myc trilogy: lord of RNA polymerases. Nature Cell Biol. 7, 215–217 (2005).
Nakaya, K. et al. Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array. Oncogene 26 Feb 2007 (doi:10.1038/sj.onc.1210330).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Katoh, Y. & Katoh, M. Comparative integromics on FAT1, FAT2, FAT3 and FAT4. Int. J. Mol. Med. 18, 523–528 (2006).
Trofatter, J. A. et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72, 791–800 (1993).
Ruttledge, M. H. et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nature Genet. 6, 180–184 (1994).
Yoo, N. J. et al. Mutational analysis of salvador gene in human carcinomas. APMIS 111, 595–598 (2003).
St John, M. A. et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nature Genet. 21, 182–186 (1999).
Hisaoka, M., Tanaka, A. & Hashimoto, H. Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab. Invest. 82, 1427–1435 (2002).
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Glossary
- FERM domain
-
An amino-acid homology domain that was first identified in the Band 4.1 family of proteins (4.1, ezrin, radixin and moesin). This domain typically localizes to cell surfaces and crosslinks the actin cytoskeleton with the plasma membrane.
- Protocadherin
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A member of the largest subgroup of the cadherin family. Protocadherins have extensive extracellular domains and cytoplasmic domains that vary widely from each other and from the domains of classic cadherins.
- Adherens junction
-
An adhesive junction that is commonly found between epithelial cells. It is maintained by extracellular interactions of cadherin proteins and intracellular interactions with the actin cytoskeleton.
- Desmosomal junction
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An adhesive junction between epithelial cells that is located basally to adherens junctions. It is maintained by extracellular interactions of cadherin proteins that are anchored intracellularly to intermediate filaments.
- Unconventional myosin
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A member of a class of motor proteins that interact with the actin cytoskeleton and have been shown to direct intracellular vesicle transport and to contribute to neurosensory function.
- Interommatidial cell
-
One of a single layer of pigment cells that surround each ommatidia in the adult eye of Drosophila melanogaster. These cells are produced in excess before being reduced by apoptosis during insect development.
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Saucedo, L., Edgar, B. Filling out the Hippo pathway. Nat Rev Mol Cell Biol 8, 613–621 (2007). https://doi.org/10.1038/nrm2221
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DOI: https://doi.org/10.1038/nrm2221
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