title: ANKS6 is the critical activator of NEK8 kinase in embryonic situs determination and organ patterning.
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, 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.
authors.affiliation: 1] Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 568, Boston, Massachussetts 02115, USA [2] Renal Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA [3] Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachussetts 02215, USA.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Czarnecki
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Gabriel
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Manning
authors.affiliation: 1] Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 568, Boston, Massachussetts 02115, USA [2] Renal Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Sergeev
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Lemke
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Nikolai T
authors.initials: NT
authors.lastname: Klena
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachussetts 01655, USA.
authors.forename: Jovenal T
authors.initials: JT
authors.lastname: San Agustin
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
authors.forename: Maija K
authors.initials: MK
authors.lastname: Garnaas
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Francis
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Tobita
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachussetts 01655, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pazour
authors.affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Cecilia W
authors.initials: CW
authors.lastname: Lo
authors.affiliation: 1] Genetics Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA [2] Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, Washington 98101, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.affiliation: 1] Department of Systems Biology, Harvard Medical School, 4 Blackfan Circle, HIM 568, Boston, Massachussetts 02115, USA [2] Renal Division, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000235:genetics / Q000502:physiology; D009154:Mutation; D000072379:NIMA-Related Kinases; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C000607697:ANKS6 protein, mouse; C532259:Anks6 protein, rat; D002352:Carrier Proteins; C114503:INVS protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D000072379:NIMA-Related Kinases; C499219:Nek8 protein, mouse; D017346:Protein Serine-Threonine Kinases; C528697:nephrocystin-3, human; D016547:Kinesins