2023
The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Onuchic L, Padovano V, Schena G, Rajendran V, Dong K, Shi X, Pandya R, Rai V, Gresko N, Ahmed O, Lam T, Wang W, Shen H, Somlo S, Caplan M. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nature Communications 2023, 14: 1790. PMID: 36997516, PMCID: PMC10063565, DOI: 10.1038/s41467-023-37449-1.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDisease Models, AnimalHumansKidneyMiceMitochondrial ProteinsNADP Transhydrogenase, AB-SpecificPolycystic Kidney, Autosomal DominantTRPP Cation ChannelsConceptsPolycystin-1Nicotinamide nucleotide transhydrogenaseTerminal tailCystic phenotypeAutosomal dominant polycystic kidney diseaseCyst cell proliferationC-terminal domainAmino acid residuesLethal monogenic disorderC-terminal cleavageNucleotide transhydrogenaseAcid residuesMitochondrial functionTransgenic expressionPKD1 geneRedox stateShort fragmentsCell proliferationMonogenic disordersDominant polycystic kidney diseasePolycystic kidney diseaseGene therapy strategiesProteinPhenotypeFragments
2022
Polycystin-2 in the Endoplasmic Reticulum: Bending Ideas about the Role of the Cilium
Caplan MJ. Polycystin-2 in the Endoplasmic Reticulum: Bending Ideas about the Role of the Cilium. Journal Of The American Society Of Nephrology 2022, 33: 1433-1434. PMID: 35906088, PMCID: PMC9342637, DOI: 10.1681/asn.2022050557.Peer-Reviewed Original Research
2021
β3 adrenergic receptor as potential therapeutic target in ADPKD
Schena G, Carmosino M, Chiurlia S, Onuchic L, Mastropasqua M, Maiorano E, Schena FP, Caplan MJ. β3 adrenergic receptor as potential therapeutic target in ADPKD. Physiological Reports 2021, 9: e15058. PMID: 34676684, PMCID: PMC8531837, DOI: 10.14814/phy2.15058.Peer-Reviewed Original ResearchConceptsAutosomal dominant polycystic kidney diseaseΒ3-ARΒ3-adrenergic receptorTherapeutic targetKidney/body weight ratioΒ3-AR levelSympathetic nerve activityBody weight ratioType 2 receptorCyst-lining epithelial cellsDominant polycystic kidney diseaseRenal tubular cellsNovel therapeutic targetCyclic AMP accumulationPotential therapeutic targetVasopressin type 2 receptorHuman renal tissuePolycystic kidney diseaseFluid-filled cystsADPKD mouse modelNerve activityKidney functionKidney diseaseRenal parenchymaHealthy controls
2019
Holding open the door reveals a new view of polycystin channel function
Caplan MJ. Holding open the door reveals a new view of polycystin channel function. EMBO Reports 2019, 20: embr201949156. PMID: 31556469, PMCID: PMC6832007, DOI: 10.15252/embr.201949156.Peer-Reviewed Original ResearchMeSH KeywordsHumansIon ChannelsPolycystic Kidney, Autosomal DominantSignal TransductionTRPP Cation Channels
2018
The Polycystin Complex Reveals Its Complexity
Padovano V, Caplan MJ. The Polycystin Complex Reveals Its Complexity. Biochemistry 2018, 57: 6917-6918. PMID: 30540438, DOI: 10.1021/acs.biochem.8b01205.Peer-Reviewed Original ResearchHumansIon Channel GatingKineticsPolycystic Kidney, Autosomal DominantProtein Interaction Domains and MotifsProtein Structure, QuaternaryTRPP Cation ChannelsPolycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Merrick D, Mistry K, Wu J, Gresko N, Baggs JE, Hogenesch JB, Sun Z, Caplan MJ. Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ. Human Molecular Genetics 2018, 28: 16-30. PMID: 30215740, PMCID: PMC6298236, DOI: 10.1093/hmg/ddy322.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBone DevelopmentCell DifferentiationE1A-Associated p300 ProteinGene Expression RegulationGenes, RegulatorHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsKidneyModels, AnimalMorpholinosOsteoblastsOsteogenesisPolycystic Kidney, Autosomal DominantTrans-ActivatorsTranscription FactorsTranscriptional Coactivator with PDZ-Binding Motif ProteinsTRPP Cation ChannelsZebrafishZebrafish ProteinsConceptsC-terminal tailCurly tail phenotypePolycystin-1Tail phenotypeTranscriptional coactivator TAZMessenger RNARunx2 transcriptional activityBone developmentTranscription factor Runx2Co-regulatory proteinsPkd1 mutant miceEssential coactivatorTranscriptional pathwaysTranscriptional activityOsteoblast differentiationKey mechanistic linkTAZPhysiological functionsPKD1 geneMechanistic linkRunx2MorpholinoPhenotypeMutant miceAutosomal dominant polycystic kidney diseaseMetabolism and mitochondria in polycystic kidney disease research and therapy
Padovano V, Podrini C, Boletta A, Caplan MJ. Metabolism and mitochondria in polycystic kidney disease research and therapy. Nature Reviews Nephrology 2018, 14: 678-687. PMID: 30120380, DOI: 10.1038/s41581-018-0051-1.Peer-Reviewed Original ResearchConceptsPolycystic kidney disease 1Polycystin-1Autosomal dominant polycystic kidney diseaseHallmark of ADPKDFluid-filled renal cystsPolycystin proteinsADPKD cellsPKD genesMolecular mechanismsOxidative phosphorylationCell metabolismRegulatory rolePhysiological functionsADPKD pathogenesisEnergy metabolismPotential therapeutic targetMonogenic diseasesEnergy productionMitochondriaDominant polycystic kidney diseasePolycystic kidney diseaseTherapeutic targetMutationsAlternative pathwayMetabolism
2016
The tail of polycystin-1 pays the kidney a complement
Caplan MJ. The tail of polycystin-1 pays the kidney a complement. American Journal Of Physiology. Renal Physiology 2016, 310: f1180-f1181. PMID: 27009337, DOI: 10.1152/ajprenal.00141.2016.Peer-Reviewed Original Research
2013
Polycystin-1 cleavage and the regulation of transcriptional pathways
Merrick D, Bertuccio CA, Chapin HC, Lal M, Chauvet V, Caplan MJ. Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatric Nephrology 2013, 29: 505-511. PMID: 23824180, PMCID: PMC3844055, DOI: 10.1007/s00467-013-2548-y.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGene Expression RegulationHumansMutationPolycystic Kidney, Autosomal DominantTranscription, GeneticTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseaseFluid-filled renal cystsPolycystin-2Transcriptional pathwaysPolycystin-1Primary ciliaProtein productsPhysiological functionsCommon genetic causeParent proteinProteolytic cleavageCleavage fragmentsGenetic causeGenesEnd-stage renal diseaseDominant polycystic kidney diseasePolycystic kidney diseaseBiological activityPathwayRenal diseaseKidney diseaseCleavageRenal parenchymaFragmentsRenal cystsPolycystin-1C terminus cleavage and its relation with polycystin-2, two proteins involved in polycystic kidney disease.
Bertuccio CA, Caplan MJ. Polycystin-1C terminus cleavage and its relation with polycystin-2, two proteins involved in polycystic kidney disease. Medicina 2013, 73: 155-62. PMID: 23570767.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCalcium ChannelsCell NucleusCell ProliferationCyclic AMPHumansKidney TubulesMutationPolycystic Kidney, Autosomal DominantTRPP Cation ChannelsConceptsPolycystin-1Polycystin-2Autosomal dominant polycystic kidney diseaseTerminal cytoplasmic tailProtein sortingNormal tubulogenesisPolycystic kidney diseaseProtein functionCytoplasmic tailTerminal tailCommon genetic causeCystogenic processExtracellular matrixDifferentiation mechanismsCellular proliferationGenetic causeMultiple cleavagesDominant polycystic kidney diseasePathwayHigh proliferative rateCleavageProliferative rateSecretory characteristicsGenesTubulogenesis
2011
The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism
Merrick D, Chapin H, Baggs JE, Yu Z, Somlo S, Sun Z, Hogenesch JB, Caplan MJ. The γ-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism. Developmental Cell 2011, 22: 197-210. PMID: 22178500, PMCID: PMC3264829, DOI: 10.1016/j.devcel.2011.10.028.Peer-Reviewed Original ResearchMeSH KeywordsAmyloid Precursor Protein SecretasesAnimalsApoptosisCell ProliferationCells, CulturedCystsEmbryo, NonmammalianHumansImmunoblottingImmunoprecipitationKidneyP300-CBP Transcription FactorsPhenotypePolycystic Kidney, Autosomal DominantTCF Transcription FactorsTranscription Factor CHOPTranscriptional ActivationTRPP Cation ChannelsWnt Signaling PathwayZebrafishConceptsCarboxy-terminal tailPolycystin-1P300-dependent mechanismTranscription factor TCFTranscriptional coactivator p300Cultured renal epithelial cellsΓ-secretase-mediated cleavageAutosomal dominant polycystic kidney diseaseRenal epithelial cellsTranscriptional activationZebrafish embryosCoactivator p300Γ-secretase activityNormal growth ratePKD1 expressionNull cellsProtein fragmentsCyst formationΓ-secretase inhibitionCHOP pathwayApoptosisEpithelial cellsCleavage productsPolycystic kidney diseaseExpressionMacrophages Promote Cyst Growth in Polycystic Kidney Disease
Karihaloo A, Koraishy F, Huen SC, Lee Y, Merrick D, Caplan MJ, Somlo S, Cantley LG. Macrophages Promote Cyst Growth in Polycystic Kidney Disease. Journal Of The American Society Of Nephrology 2011, 22: 1809-1814. PMID: 21921140, PMCID: PMC3187181, DOI: 10.1681/asn.2011010084.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, LyCell LineCell MovementCell ProliferationChemokine CCL2Chemokine CXCL16Chemokine CXCL6MacrophagesMiceMice, Inbred C57BLPolycystic Kidney, Autosomal DominantConceptsPolycystic kidney diseaseCyst-lining cellsKidney diseaseCyst growthPkd1-deficient cellsContribution of inflammationMacrophage-depleted miceVehicle-treated controlsPostnatal day 10Renal functionInflammatory componentIschemic injuryOrthologous modelCre miceCystic areasLiposomal clodronateCyst progressionRenal parenchymaCystic indexTubular cellsDay 10Therapeutic potentialDay 24Macrophage migrationMacrophagesActivating AMP-activated protein kinase (AMPK) slows renal cystogenesis
Takiar V, Nishio S, Seo-Mayer P, King JD, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ. Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 2462-2467. PMID: 21262823, PMCID: PMC3038735, DOI: 10.1073/pnas.1011498108.Peer-Reviewed Original ResearchConceptsCystic fibrosis transmembrane conductance regulatorRenal cystogenesisProtein kinaseAutosomal dominant polycystic kidney diseaseFibrosis transmembrane conductance regulatorTransmembrane conductance regulatorEpithelial cellsCyst epithelial cellsRenal cyst developmentCyst-lining epithelial cellsAMPK activationConductance regulatorRapamycin (mTOR) pathwayMammalian targetPharmacological activatorsChloride channelsMTOR pathwayCystogenesisCyst developmentKinaseAMPKContext of ADPKDSignificant arrestDominant polycystic kidney diseasePolycystic kidney disease
2010
Polycystic kidney disease: Pathogenesis and potential therapies
Takiar V, Caplan MJ. Polycystic kidney disease: Pathogenesis and potential therapies. Biochimica Et Biophysica Acta 2010, 1812: 1337-1343. PMID: 21146605, PMCID: PMC3139769, DOI: 10.1016/j.bbadis.2010.11.014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCiliaCyclic AMPCyst FluidHumansPolycystic Kidney, Autosomal DominantSignal TransductionTRPP Cation ChannelsConceptsAutosomal dominant polycystic kidney diseasePolycystic kidney diseaseKidney diseaseRenal tubular epithelial cellsDominant polycystic kidney diseaseNovel therapeutic targetTubular epithelial cellsFluid-filled cystsRenal cyst formationRenal functionTreatment of PKDPathogenetic pathwaysPotential therapyTherapeutic targetDisease pathogenesisClinical therapyCyst formationInherited conditionEpithelial cellsDiseasePathogenesisTherapyPrimary ciliaCystsParenchymaThe cell biology of polycystic kidney disease
Chapin HC, Caplan MJ. The cell biology of polycystic kidney disease. Journal Of Cell Biology 2010, 191: 701-710. PMID: 21079243, PMCID: PMC2983067, DOI: 10.1083/jcb.201006173.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGTP-Binding ProteinsHumansKidneyModels, MolecularPolycystic Kidney, Autosomal DominantSignal TransductionTRPP Cation ChannelsWnt ProteinsConceptsCell growth controlCell biological processesPolycystic kidney diseaseCell biologyBiological processesGrowth controlPKD2 geneFluid-filled cystsNovel therapeutic targetGenetic defectsAutosomal dominant polycystic kidney diseaseCommon genetic disorderNormal renal tubulesDominant polycystic kidney diseaseGenetic disordersTherapeutic targetDisease pathogenesisKidney diseaseMorphogenesisGenesNew lightPKD1BiologyMutationsRenal tubulesPolycystin-1 Surface Localization Is Stimulated by Polycystin-2 and Cleavage at the G Protein-coupled Receptor Proteolytic Site
Chapin HC, Rajendran V, Caplan MJ. Polycystin-1 Surface Localization Is Stimulated by Polycystin-2 and Cleavage at the G Protein-coupled Receptor Proteolytic Site. Molecular Biology Of The Cell 2010, 21: 4338-4348. PMID: 20980620, PMCID: PMC3002387, DOI: 10.1091/mbc.e10-05-0407.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell MembraneCiliaFluorescent Antibody TechniqueHEK293 CellsHumansImmunoprecipitationKidneyLLC-PK1 CellsMutationPolycystic Kidney, Autosomal DominantProtein BindingProtein IsoformsProtein Processing, Post-TranslationalProtein Structure, TertiaryProtein TransportSwineTRPP Cation ChannelsConceptsG-protein-coupled receptor proteolytic siteGPS cleavagePC2 channel activitySurface deliveryChannel activityProteolytic siteSurface localizationPlasma membrane localizationC-terminal tailHuman embryonic kidney 293 cellsEmbryonic kidney 293 cellsPC2 mutationsKidney 293 cellsMembrane localizationSecretory pathwayMembrane proteinsBinding partnerTerminal tailPolycystin-2Effect of PC2Plasma membraneCiliary membraneTRP familyLLC-PK cellsCation channels
2008
Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling
Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ. Polycystin-1 C-terminal tail associates with β-catenin and inhibits canonical Wnt signaling. Human Molecular Genetics 2008, 17: 3105-3117. PMID: 18632682, PMCID: PMC2722884, DOI: 10.1093/hmg/ddn208.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBeta CateninBinding SitesCell LineCell NucleusCHO CellsCricetinaeCricetulusGene Expression ProfilingGene Expression RegulationHumansLigandsOligonucleotide Array Sequence AnalysisPeptide FragmentsPolycystic Kidney, Autosomal DominantRecombinant ProteinsSignal TransductionSystems BiologyTCF Transcription FactorsTransfectionTRPP Cation ChannelsWnt ProteinsConceptsC-terminal tailCanonical WntPolycystin-1Wnt-dependent signalingDNA microarray analysisDependent gene transcriptionN-terminal portionInhibits canonical WntTCF proteinsT-cell factorAutosomal dominant polycystic kidney disease (ADPKD) casesMotif presentGene transcriptionDevelopmental processesMicroarray analysisWntPKD1 geneΒ-cateninNovel mechanism
2005
Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells*
Grimm DH, Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ. Polycystin-2 Regulates Proliferation and Branching Morphogenesis in Kidney Epithelial Cells*. Journal Of Biological Chemistry 2005, 281: 137-144. PMID: 16278216, DOI: 10.1074/jbc.m507845200.Peer-Reviewed Original ResearchConceptsPolycystin-2Kidney epithelial cellsPolycystin-1Cell proliferationRegulation of tubulogenesisWild-type proteinMultiple fluid-filled cystsAutosomal dominant polycystic kidney diseaseTubule formationEpithelial cellsExtracellular-related kinaseRegulatory machineryPolycystin proteinsBranching morphogenesisNegative regulatorRespective proteinsGenes PKD1Regulates ProliferationChannel mutantsMorphogenesisFluid-filled cystsCell growthProper growthChannel activityProtein
2004
Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus
Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hieseberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ. Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. Journal Of Clinical Investigation 2004, 114: 1433-1443. PMID: 15545994, PMCID: PMC525739, DOI: 10.1172/jci21753.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCell LineCell NucleusChlorocebus aethiopsCHO CellsCOS CellsCricetinaeCricetulusDogsEmbryo, MammalianEpithelial CellsKidney TubulesMembrane ProteinsMiceMice, TransgenicPolycystic Kidney, Autosomal DominantProteinsSequence DeletionSignal TransductionStress, MechanicalTranscription Factor AP-1TRPP Cation ChannelsConceptsC-terminal tailAutosomal dominant polycystic kidney diseaseCell-matrix interactionsCiliary signalingSecond genePolycystin-2Polycystin-1C-terminusNovel pathwayProteolytic cleavageNuclear translocationMechanical stimuliGenesDominant polycystic kidney diseasePolycystic kidney diseasePrecise mechanismCleavageTerminusSignalingTranslocationNucleusPathway
1996
Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells.
Brill SR, Ross KE, Davidow CJ, Ye M, Grantham JJ, Caplan MJ. Immunolocalization of ion transport proteins in human autosomal dominant polycystic kidney epithelial cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 1996, 93: 10206-10211. PMID: 8816777, PMCID: PMC38362, DOI: 10.1073/pnas.93.19.10206.Peer-Reviewed Original ResearchConceptsCyst epithelial cellsEpithelial cellsCystic fibrosis transmembrane conductance regulatorIon transport proteinsFibrosis transmembrane conductance regulatorK-ATPaseApical cystic fibrosis transmembrane conductance regulatorTransmembrane conductance regulatorKidney epithelial cellsK-ATPase proteinRenal epithelial cellsCFTR proteinTransport proteinsConductance regulatorIntracellular structuresFluid-filled cystsApical membraneForskolin treatmentBasolateral surfacePermeable filter supportsApical surfaceProteinCl- channelsApical labelingAutosomal dominant polycystic kidney disease