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ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning

Author

Listed:
  • Peter G. Czarnecki

    (Harvard Medical School
    Brigham and Women’s Hospital
    Beth Israel Deaconess Medical Center)

  • George C. Gabriel

    (University of Pittsburgh School of Medicine)

  • Danielle K. Manning

    (Brigham and Women’s Hospital)

  • Mikhail Sergeev

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • Kristi Lemke

    (University of Pittsburgh School of Medicine)

  • Nikolai T. Klena

    (University of Pittsburgh School of Medicine)

  • Xiaoqin Liu

    (University of Pittsburgh School of Medicine)

  • Yu Chen

    (University of Pittsburgh School of Medicine)

  • You Li

    (University of Pittsburgh School of Medicine)

  • Jovenal T. San Agustin

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Maija K. Garnaas

    (Brigham and Women’s Hospital)

  • Richard J. Francis

    (University of Pittsburgh School of Medicine)

  • Kimimasa Tobita

    (University of Pittsburgh School of Medicine)

  • Wolfram Goessling

    (Brigham and Women’s Hospital)

  • Gregory J. Pazour

    (Program in Molecular Medicine, University of Massachusetts Medical School)

  • Cecilia W. Lo

    (University of Pittsburgh School of Medicine)

  • David R. Beier

    (Brigham and Women’s Hospital
    Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington 98101, USA)

  • Jagesh V. Shah

    (Harvard Medical School
    Brigham and Women’s Hospital)

Abstract

The ciliary kinase NEK8 plays a critical role in situs determination and cystic kidney disease, yet its exact function remains unknown. In this study, we identify ANKS6 as a target and activator of NEK8. ANKS6 requires NEK8 for localizing to the ciliary inversin compartment (IC) and activates NEK8 by binding to its kinase domain. Here we demonstrate the functional importance of this interaction through the analysis of two novel mouse mutations, Anks6Streaker and Nek8Roc. Both display heterotaxy, cardiopulmonary malformations and cystic kidneys, a syndrome also characteristic of mutations in Invs and Nphp3, the other known components of the IC. The Anks6Strkr mutation decreases ANKS6 interaction with NEK8, precluding NEK8 activation. The Nek8Roc mutation inactivates NEK8 kinase function while preserving ANKS6 localization to the IC. Together, these data reveal the crucial role of NEK8 kinase activation within the IC, promoting proper left–right patterning, cardiopulmonary development and renal morphogenesis.

Suggested Citation

  • Peter G. Czarnecki & George C. Gabriel & Danielle K. Manning & Mikhail Sergeev & Kristi Lemke & Nikolai T. Klena & Xiaoqin Liu & Yu Chen & You Li & Jovenal T. San Agustin & Maija K. Garnaas & Richard , 2015. "ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning," Nature Communications, Nature, vol. 6(1), pages 1-13, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7023
    DOI: 10.1038/ncomms7023
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