CellMetabolismReviewWNKKinaseSignalinginIonHomeostasisandHumanDiseaseMasoudShekarabi,1JinweiZhang,2,3ArjunR.Khanna,4,5DavidH.Ellison,6,7EricDelpire,8andKristopherT.Kahle9,*1DepartmentofNeuroscience,LewisKatzSchoolofMedicineatTempleUniversity,Philadelphia,PA19140,USA2DepartmentsofNeurosurgery,CentersforMendelianGenomics,YaleSchoolofMedicine,NewHaven,CT06477,USA3MRCProteinPhosphorylationandUbiquitylationUnit,CollegeofLifeSciences,UniversityofDundee,DundeeDD15EH,Scotland,UK4DepartmentofNeurosurgery,MassachusettsGeneralHospital,Boston,MA02114,USA5DepartmentofNeurosurgery,HarvardMedicalSchool,Boston,MA02115,USA6DivisionofNephrology&Hypertension,DepartmentofMedicine,OregonHealth&ScienceUniversity,Portland,Oregon97239,USA7VAPortlandHealthCareSystem,Portland,OR97239,USA8DepartmentofAnesthesiology,VanderbiltUniversitySchoolofMedicine,Nashville,TN37232,USA9DepartmentsofNeurosurgery,Pediatrics,andCellular&MolecularPhysiology,CentersforMendelianGenomics,YaleSchoolofMedicine,NewHaven,CT06477,USA*Correspondence:kristopher.kahle@yale.eduhttp://dx.doi.org/10.1016/j.cmet.2017.01.007WNKkinases,alongwiththeirupstreamregulators(CUL3/KLHL3)anddownstreamtargets(theSPAK/OSR1kinasesandthecation-Cl�cotransporters[CCCs]),compriseasignalingcascadeessentialforionhomeosta-sisinthekidneyandnervoussystem.RecentworkhasfurtheredourunderstandingoftheWNKsinepithelialtransport,cellvolumehomeostasis,andGABAsignaling,anduncoverednovelrolesforthispathwayinim-munecellfunctionandcellproliferation.IntroductionHomeostasisoftheintracellularionicmilieuisessentialfortheproperfunctioningofallcellsandadiversegroupofcellularprocesses.ThemechanismsresponsibleforthehomeostasisoftheintracellularCl�concentration[Cl�]i,forexample,signifi-cantlyimpactstherateoffluidsecretionorabsorptionacrossepithelia,howredbloodcellscounteractpotentiallydamagingosmotic-inducedcellswellingorshrinkage,andwhethertheGABAneurotransmitterexcitesorinhibitspost-synapticneu-rons.Accordingly,[Cl�]iishighlyregulatedbysignalingmole-culestha...
