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An evolutionary shift in the regulation of the Hippo pathway between mice and flies

Oncogene volume 33, pages 1218–1228 (2014)Cite this article

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Abstract

The Hippo pathway plays a key role in controlling organ growth in many animal species and its deregulation is associated with different types of cancer. Understanding the regulation of the Hippo pathway and discovering upstream regulators is thus a major quest. Interestingly, while the core of the Hippo pathway contains a highly conserved kinase cascade, different components have been identified as upstream regulators in Drosophila and vertebrates. However, whether the regulation of the Hippo pathway is indeed different between Drosophila and vertebrates or whether these differences are due to our limited analysis of these components in different organisms is not known. Here we show that the mouse Fat4 cadherin, the ortholog of the Hippo pathway regulator Fat in Drosophila, does not apparently regulate the Hippo pathway in the murine liver. In fact, we uncovered an evolutionary shift in many of the known upstream regulators at the base of the arthropod lineage. In this evolutionary transition, Fat and the adaptor protein Expanded gained novel domains that connected them to the Hippo pathway, whereas the cell-adhesion receptor Echinoid evolved as a new protein. Subsequently, the junctional adaptor protein Angiomotin (Amot) was lost and the downstream effector Yap lost its PDZ-binding motif that interacts with cell junction proteins. We conclude that fundamental differences exist in the upstream regulatory mechanisms of Hippo signaling between Drosophila and vertebrates.

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Acknowledgements

We are grateful to Drs Alfred Handler, Giuliano Gasperi and Stephen Richards of the Medfly Whole Genome Sequencing Consortium for providing the draft genome sequence of Ceratitis capitata. We thank Lisa McCord for assistance with graphical representation, and also Dr Ryan Udan, Dr Maria Willecke and Chunyao Tao for help in performing the screen, experimental input and valuable discussions. This study was supported in part by grants from Department of Defense (NF093145 to DP) and from the National Institute of Health (GM067997 to GH). QC is a recipient of a Breast Cancer Research Postdoctoral Fellowship from the Department of Defense (BC093902). DP is an investigator of the Howard Hughes Medical Institute.

Author contributions

WB initiated and designed the work, performed evolutionary tracing of the different genes and analyzed the results; WB and CLC performed and analyzed the Drosophila experiments; QC designed, performed and analyzed the mouse experiments; DJP designed and analyzed the mouse experiments; MS provided analysis for the Yap/Yki and Amot data; AK performed evolutionary tracing; GH led and designed the experiments; and WB and GH wrote the manuscript with input from all other authors.

Author information

Author notes

  1. C-L Chen

    Present address: 8Current address: Department of Genetics, Harvard Medical School, Boston, MA, USA.,

Authors and Affiliations

  1. Vlaams Instituut voor Biotechnologie (VIB) Center for the Biology of Disease, Leuven, Belgium

    W Bossuyt & G Halder

  2. Kuleuven, Center for Human Genetics, Leuven, Belgium

    W Bossuyt & G Halder

  3. The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    W Bossuyt, C-L Chen & G Halder

  4. Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Q Chen & D Pan

  5. Weis Center for Research, Laboratory of Signal Transduction, Geisinger Clinic, Danville, PA, USA

    M Sudol

  6. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    H McNeill

  7. Department of Evolution and Ecology, University of California-Davis, Davis, CA, USA

    A Kopp

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Bossuyt, W., Chen, CL., Chen, Q. et al. An evolutionary shift in the regulation of the Hippo pathway between mice and flies. Oncogene 33, 1218–1228 (2014). https://doi.org/10.1038/onc.2013.82

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  • DOI: https://doi.org/10.1038/onc.2013.82

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