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Riquiqui and Minibrain are regulators of the Hippo pathway downstream of Dachsous

Nature Cell Biology volume 15, pages 11761185 (2013) | Download Citation

Abstract

The atypical cadherins Fat (Ft) and Dachsous (Ds) control tissue growth through the Salvador–Warts–Hippo (SWH) pathway, and also regulate planar cell polarity and morphogenesis. Ft and Ds engage in reciprocal signalling as both proteins can serve as receptor and ligand for each other. The intracellular domains (ICDs) of Ft and Ds regulate the activity of the key SWH pathway transcriptional co-activator protein Yorkie (Yki). Signalling from the FtICD is well characterized and controls tissue growth by regulating the abundance of the Yki-repressive kinase Warts (Wts). Here we identify two regulators of the Drosophila melanogaster SWH pathway that function downstream of the DsICD: the WD40 repeat protein Riquiqui (Riq) and the DYRK-family kinase Minibrain (Mnb). Ds physically interacts with Riq, which binds to both Mnb and Wts. Riq and Mnb promote Yki-dependent tissue growth by stimulating phosphorylation-dependent inhibition of Wts. Thus, we describe a previously unknown branch of the SWH pathway that controls tissue growth downstream of Ds.

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Acknowledgements

We thank C. House for assistance with mass spectrometry, J. Lin and K. Hannan for expertise with kinase assays and S. Blair (University of Madison, Wisconsin, USA), I. Edery (Rutgers University, USA), C. House (Peter MacCallum Cancer Centre, Australia), K. Irvine (Rutgers University, USA), D. Pan (Johns Hopkins University, USA), M. Simon (Stanford University, USA), D. Strutt, University of Sheffield, UK), N. Tapon (Cancer Research UK, UK), F. Tejedor (Universidad Miguel Hernandez, Spain), K. Yu (Korea Research Institute of Bioscience and Biotechnology), the Developmental Studies Hybridoma Bank, the Vienna Drosophila RNAi Center, the Australian Drosophila Research Support Facility (www.ozdros.com), the National Institute of Genetics and the Bloomington Stock Centre for fly stocks, plasmids and antibodies. K.F.H. is a Sylvia and Charles Viertel Senior Medical Research Fellow. This research was supported by a Project Grant from the National Health and Medical Research Council of Australia, and by NIH grants GM097727 and CA156734 and NSF grant 0640700 to A.V. Mass spectrometry was performed at the Taplin Facility, Harvard Medical School, USA and Bio21, University of Melbourne, Australia.

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Affiliations

  1. Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, Victoria 3002, Australia

    • Joffrey L. Degoutin
    • , Claire C. Milton
    • , Eefang Yu
    •  & Kieran F. Harvey
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia

    • Joffrey L. Degoutin
    • , Claire C. Milton
    • , Eefang Yu
    •  & Kieran F. Harvey
  3. Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia

    • Claire C. Milton
    •  & Kieran F. Harvey
  4. Department of Biology, University of Massachusetts Boston, Boston, Massachusetts 02125, USA

    • Marla Tipping
    • , Liu Yang
    •  & Alexey Veraksa
  5. Polarity, Division and Morphogenesis Team, Institut Curie, CNRS UMR 3215, INSERM U934, 26 Rue d’Ulm, 75248 Paris Cedex 05, France

    • Floris Bosveld
    •  & Yohanns Bellaiche

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Contributions

J.L.D. and C.C.M. performed Drosophila genetic experiments. J.L.D. and E.Y. carried out biochemistry and molecular biology experiments. M.T., L.Y. and A.V. performed affinity purification and mass spectrometry. F.B. and Y.B. analysed Dachs localization in the pupal notum. J.L.D. and K.F.H. designed experiments, analysed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kieran F. Harvey.

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https://doi.org/10.1038/ncb2829

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