Featured Publications
Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein
Park JS, Choi J, Cao L, Mohanty J, Suzuki Y, Park A, Baker D, Schlessinger J, Lee S. Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein. Cell Reports 2022, 41: 111545. PMID: 36288716, PMCID: PMC9636537, DOI: 10.1016/j.celrep.2022.111545.Peer-Reviewed Original ResearchMeSH KeywordsFibroblast Growth FactorsHormonesLigandsProtein IsoformsReceptors, Fibroblast Growth FactorSignal TransductionConceptsFibroblast growth factor receptorC isoformsFibroblast growth factor ligandsLigand-binding regionSilico design strategyIsoform-specific inhibitionGrowth factor ligandsAlternative splicingCellular signalingRegulated processGrowth factor receptorDevelopment of therapeuticsFGFR isoformsFactor ligandCellular analysisFactor receptorMechanistic insightsKlotho proteinSpecific interactionsMB7Distinct subsetsHigh affinitySplicingSignalingFGFStructures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity
Kuzina ES, Ung PM, Mohanty J, Tome F, Choi J, Pardon E, Steyaert J, Lax I, Schlessinger A, Schlessinger J, Lee S. Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 7819-7824. PMID: 30944224, PMCID: PMC6475419, DOI: 10.1073/pnas.1822055116.Peer-Reviewed Original ResearchConceptsFGF receptorsPleiotropic cellular responsesFibroblast growth factor (FGF) familyPrimary high-affinity receptorsKlotho proteinChimeric mutantsGrowth factor familyCatalytic subunitFGFR functionRegulatory interactionsTerminal tailPleiotropic cellular effectsFactor familyP motifS motifExtracellular domainMolecular mechanismsIntracellular signalingCellular responsesSame binding siteCellular effectsGeneral mechanismEndocrine FGFsBinary complexBinding sitesStructures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling
Lee S, Choi J, Mohanty J, Sousa LP, Tome F, Pardon E, Steyaert J, Lemmon MA, Lax I, Schlessinger J. Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling. Nature 2018, 553: 501-505. PMID: 29342135, PMCID: PMC6594174, DOI: 10.1038/nature25010.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCrystallography, X-RayExtracellular SpaceFibroblast Growth Factor-23Fibroblast Growth FactorsGlycoside HydrolasesHEK293 CellsHumansKlotho ProteinsLigandsMembrane ProteinsModels, MolecularProtein BindingProtein DomainsReceptors, Fibroblast Growth FactorSignal TransductionSubstrate Specificity
2020
FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho
Suzuki Y, Kuzina E, An SJ, Tome F, Mohanty J, Li W, Lee S, Liu Y, Lax I, Schlessinger J. FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 31800-31807. PMID: 33257569, PMCID: PMC7749347, DOI: 10.1073/pnas.2018554117.Peer-Reviewed Original ResearchMeSH KeywordsBinding SitesCalcinosisCell MembraneFibroblast Growth Factor-23Fibroblast Growth FactorsGlucuronidaseHEK293 CellsHumansHyperostosis, Cortical, CongenitalHyperphosphatemiaImmunoglobulin Fc FragmentsKlotho ProteinsMutationOsteomalaciaProtein BindingProtein DomainsProtein MultimerizationRecombinant Fusion ProteinsRickets, HypophosphatemicConceptsFGF receptorsTotal internal reflection fluorescence microscopyChimeric receptor moleculesReflection fluorescence microscopyBinding sitesDisulfide bridge formationCritical metabolic processesMAPK responseCytoplasmic domainGrowth factor familyTerminal tailFactor familyKinase activationSimilar binding affinitiesExtracellular domainFGFR1 activationTandem repeatsMetabolic processesDisulfide bridgesCell surfaceDistinct ligandsCell membraneFluorescence microscopyDistinct high-affinity binding sitesPhosphate homeostasis
2015
FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis
Perry RJ, Lee S, Ma L, Zhang D, Schlessinger J, Shulman GI. FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis. Nature Communications 2015, 6: 6980. PMID: 25916467, PMCID: PMC4413509, DOI: 10.1038/ncomms7980.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl Coenzyme AAdrenocorticotropic HormoneAnimalsCorticosteroneDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 1Fibroblast Growth Factor 1Fibroblast Growth FactorsGlucoseHypothalamo-Hypophyseal SystemInjections, IntraventricularInsulinLipolysisLiverMalePituitary-Adrenal SystemPyruvate CarboxylaseRats, Sprague-DawleyConceptsHepatic acetyl-CoA contentFibroblast growth factor 1Whole-body lipolysisHepatic glucose productionAcetyl-CoA contentGlucose productionAwake rat modelRecombinant fibroblast growth factor 1CoA contentIntra-arterial infusionGlucose-lowering effectType 1 diabetesGrowth factor-1Mechanism of actionReverse diabetesDiabetic rodentsICV injectionIntracerebroventricular injectionPlasma ACTHHPA axisAdrenal axisRat modelGlucose metabolismCorticosterone concentrationsFGF19