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

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 J. Francis, Kimimasa Tobita, Wolfram Goessling, Gregory J. Pazour, Cecilia W. Lo (), David R. Beier () and Jagesh V. Shah ()
Additional contact information
Peter G. Czarnecki: Harvard Medical School
George C. Gabriel: University of Pittsburgh School of Medicine
Danielle K. Manning: Brigham and Women’s Hospital
Mikhail Sergeev: Harvard Medical School
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
Jagesh V. Shah: Harvard Medical School

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7023

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