2025
SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis
Perla S, Stiegler A, Yi J, Enyenihi L, Zhang L, Riaz M, An E, Qyang Y, Boggon T, Bennett A. SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2503631122. PMID: 40854126, PMCID: PMC12415285, DOI: 10.1073/pnas.2503631122.Peer-Reviewed Original ResearchConceptsKnock-in mutationSH2 domainGenetic variantsSH2 domains of SHP2Iroquois homeoboxBinding to SHP2NSML miceProtein tyrosine phosphataseHypertrophic cardiomyopathyExpression levelsPhosphorylation-deficientProtein expressionCellular SrcTranscription factor 3Tyrosine phosphataseSHP2Protein zeroRare autosomal dominant disorderLow-dose dasatinibAutosomal dominant disorderPostnatal cardiac growthExpression of Irx3Signaling AxisIRX3Factor 3
2021
Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines
Yi JS, Perla S, Huang Y, Mizuno K, Giordano FJ, Vinks AA, Bennett AM. Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines. Cardiovascular Drugs And Therapy 2021, 36: 589-604. PMID: 33689087, PMCID: PMC9270274, DOI: 10.1007/s10557-021-07169-z.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCardiomyopathy, HypertrophicDasatinibDisease Models, AnimalLEOPARD SyndromeMiceMutationConceptsHypertrophic cardiomyopathyNSML miceDasatinib treatmentLow-dose dasatinib treatmentPK propertiesMultiple lentiginesHeart tissueDasatinib-treated miceExposure-dependent inhibitionSrc homology 2 domain-containing protein tyrosine phosphatase 2Development of HCMAssessment of markersAutosomal dominant disorderNSML patientsDasatinib administrationCardiac fibrosisEffective target engagementEffective therapyConclusionThese dataMouse modelPharmacodynamic propertiesPK parametersHCM progressionDasatinibNoonan syndrome
2020
Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines
Yi JS, Perla S, Enyenihi L, Bennett AM. Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines. JCI Insight 2020, 5 PMID: 32584792, PMCID: PMC7455087, DOI: 10.1172/jci.insight.137753.Peer-Reviewed Original ResearchConceptsProtein tyrosine phosphataseTyrosyl phosphorylationNSML micePhosphorylation-defective mutantPTPN11 mutationsS6 kinase activityPZR tyrosyl phosphorylationTyrosine phosphataseS6 kinasePathophysiological signalingKinase activityShp2 interactionMutant fibroblastsSHP2Transmembrane glycoproteinMultiple lentiginesNoonan syndromeCraniofacial defectsPTPN11 geneHeart lysatesPhosphorylationSHP2 bindingMutationsNF-κB pathwayProtein zero
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