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

Czarnecki, Peter G., Gabriel, George C., Manning, Danielle K., Sergeev, Mikhail, Lemke, Kristi, Klena, Nikolai T., Liu, Xiaoqin, Chen, Yu, Li, You, Agustin, Jovenal T. San, Garnaas, Maija K., Francis, Richard J., Tobita, Kimimasa, Goessling, Wolfram, Pazour, Gregory J., Lo, Cecilia W., Beier, David R., and Shah, Jagesh V. (2015) ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning. Nature Communications, 6. 6023.

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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, Anks6(Streaker) and Nek8(Roc). 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 Anks6(Strkr) mutation decreases ANKS6 interaction with NEK8, precluding NEK8 activation. The Nek8(Roc) 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.

Item ID: 60715
Item Type: Article (Research - C1)
ISSN: 2041-1723
Copyright Information: © 2015Macmillan Publishers Limited
Funders: MRC Human Genetics Unit, US National Institutes of Health (NIH), DFG German Research Foundation
Projects and Grants: NIH U01-HL098180
Date Deposited: 23 Oct 2019 12:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1114 Paediatrics and Reproductive Medicine > 111401 Foetal Development and Medicine @ 50%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920110 Inherited Diseases (incl. Gene Therapy) @ 100%
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