2024
Regulation and signaling of the LIM domain kinases
Casanova‐Sepúlveda G, Boggon T. Regulation and signaling of the LIM domain kinases. BioEssays 2024, e2400184. PMID: 39361252, DOI: 10.1002/bies.202400184.Peer-Reviewed Original ResearchLIM domain kinaseDownstream of Rho GTPasesCofilin/actin depolymerizing factorActin cytoskeleton regulationIntra-molecular mechanismFilament severingDepolymerizing factorRho GTPasesActin depolymerizationCytoskeleton regulationRegulation mechanismKinaseLIMProteinRegulationGTPaseLIMK2LIMK1ActinEnzymeHuman healthSignalDepolymerizationCascadeMechanism120 Treatable Acute Neuroinflammatory Disease Associated with Complement Factor I Loss-of-function in the Plain Community
Reid W, Carson V, Krieger P, Stiegler A, Boggon T, Sullivan K, van den Heuvel L, Romberg N. 120 Treatable Acute Neuroinflammatory Disease Associated with Complement Factor I Loss-of-function in the Plain Community. Clinical Immunology 2024, 262: 110062. DOI: 10.1016/j.clim.2024.110062.Peer-Reviewed Original ResearchDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Sexton J, Potchernikov T, Bibeau J, Casanova-Sepúlveda G, Cao W, Lou H, Boggon T, De La Cruz E, Turk B. Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail. Nature Communications 2024, 15: 1426. PMID: 38365893, PMCID: PMC10873347, DOI: 10.1038/s41467-024-45878-9.Peer-Reviewed Original ResearchConceptsN-terminal regionActin bindingSequence requirementsLIM kinaseAnalysis of individual variantsInactivates cofilinS. cerevisiaeRegulatory tailFamily proteinsActin depolymerizationPhosphorylation sitesKinase recognitionSequence variantsInhibitory phosphorylationCofilinN-terminusIndividual variantsFunctional constraintsActinDisordered sequencesPhosphorylationSequenceBiochemical analysisSequence constraintsKinase
2023
Autoregulation of the LIM kinases by their PDZ domain
Casanova-Sepúlveda G, Sexton J, Turk B, Boggon T. Autoregulation of the LIM kinases by their PDZ domain. Nature Communications 2023, 14: 8441. PMID: 38114480, PMCID: PMC10730565, DOI: 10.1038/s41467-023-44148-4.Peer-Reviewed Original ResearchMutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Zhao S, Mekbib K, van der Ent M, Allington G, Prendergast A, Chau J, Smith H, Shohfi J, Ocken J, Duran D, Furey C, Hao L, Duy P, Reeves B, Zhang J, Nelson-Williams C, Chen D, Li B, Nottoli T, Bai S, Rolle M, Zeng X, Dong W, Fu P, Wang Y, Mane S, Piwowarczyk P, Fehnel K, See A, Iskandar B, Aagaard-Kienitz B, Moyer Q, Dennis E, Kiziltug E, Kundishora A, DeSpenza T, Greenberg A, Kidanemariam S, Hale A, Johnston J, Jackson E, Storm P, Lang S, Butler W, Carter B, Chapman P, Stapleton C, Patel A, Rodesch G, Smajda S, Berenstein A, Barak T, Erson-Omay E, Zhao H, Moreno-De-Luca A, Proctor M, Smith E, Orbach D, Alper S, Nicoli S, Boggon T, Lifton R, Gunel M, King P, Jin S, Kahle K. Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations. Nature Communications 2023, 14: 7452. PMID: 37978175, PMCID: PMC10656524, DOI: 10.1038/s41467-023-43062-z.Peer-Reviewed Original ResearchConceptsEphrin receptor B4Galen malformationBrain arteriovenous malformationsP120 RasGAPTransmitted variantsArteriovenous malformationsDe novo variantsSingle-cell transcriptomesSignificant burdenCerebrovascular developmentIntegrative genomic analysisEndothelial cellsVenous networkAdditional probandsMalformationsNovo variantsMissense variantsGenomic analysisDevelopmental angiogenesisVascular developmentDamaging variantsVeinRasGAPIntegrated analysisPatientsCorrection: Rho family GTPase signaling through type II p21-activated kinases
Chetty A, Ha B, Boggon T. Correction: Rho family GTPase signaling through type II p21-activated kinases. Cellular And Molecular Life Sciences 2023, 80: 334. PMID: 37880444, PMCID: PMC11073300, DOI: 10.1007/s00018-023-04938-x.Peer-Reviewed Original ResearchStructure Determination of SH2–Phosphopeptide Complexes by X-Ray Crystallography: The Example of p120RasGAP
Stiegler A, Boggon T. Structure Determination of SH2–Phosphopeptide Complexes by X-Ray Crystallography: The Example of p120RasGAP. Methods In Molecular Biology 2023, 2705: 77-89. PMID: 37668970, PMCID: PMC11059313, DOI: 10.1007/978-1-0716-3393-9_5.Peer-Reviewed Original ResearchConceptsSrc homology 2SH2 domain bindsSH2 domainDomain bindsNew molecular-level insightsSH2 domain proteinsMolecular-level insightsX-ray crystallographyX-ray diffraction studiesDomain proteinsPartner proteinsHomology 2Three-dimensional structureMolecular detailsStructure determinationSuitable crystalsCanonical interactionsVapour-diffusion methodCareful structural analysisDrop vapor diffusion methodCrystallographic studiesCrystallography studiesSH2-phosphopeptide complexesDiffraction studiesP120RasGAPAuthor Correction: Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)
Ha B, Yigit S, Natarajan N, Morse E, Calderwood D, Boggon T. Author Correction: Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Communications Biology 2023, 6: 794. PMID: 37524913, PMCID: PMC10390574, DOI: 10.1038/s42003-023-05176-4.Peer-Reviewed Original ResearchDiverse p120RasGAP interactions with doubly phosphorylated partners EphB4, p190RhoGAP, and Dok1
Vish K, Stiegler A, Boggon T. Diverse p120RasGAP interactions with doubly phosphorylated partners EphB4, p190RhoGAP, and Dok1. Journal Of Biological Chemistry 2023, 299: 105098. PMID: 37507023, PMCID: PMC10470053, DOI: 10.1016/j.jbc.2023.105098.Peer-Reviewed Original ResearchConceptsSH2 domainSpatial-temporal regulationDual SH2 domainsProper vascular developmentKey binding partnerProtein familySH2 interactionsBinding partnerHuman proteinsDistinct binding interactionsWeakened affinityVascular developmentRasGAPConformational differencesP190RhoGAPSmall-angle X-ray scatteringBindingBinding interactionsAffinity measurementsEphB4DomainGTPaseDok1X-ray scatteringProteinDe novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis
Timberlake A, McGee S, Allington G, Kiziltug E, Wolfe E, Stiegler A, Boggon T, Sanyoura M, Morrow M, Wenger T, Fernandes E, Caluseriu O, Persing J, Jin S, Lifton R, Kahle K, Kruszka P. De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis. American Journal Of Human Genetics 2023, 110: 846-862. PMID: 37086723, PMCID: PMC10183468, DOI: 10.1016/j.ajhg.2023.03.017.Peer-Reviewed Original ResearchConceptsDamaging de novo variantsChromatin modificationsDe novo variantsCranial neural crest cellsGenome-wide significanceNeural crest cellsNovo variantsRetinoic acid receptor alphaExome sequence dataAcid receptor alphaTranscriptional regulationProband-parent triosGene transcriptionSequence dataCrest cellsOsteoblast differentiationCS phenotypeMendelian formsRecurrent gainsGenesRisk genesGenetic etiologyRetinoic acidReceptor alphaNeurodevelopmental disorders169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation
Mekbib K, Zhao S, Nelson-Williams C, Prendergast A, Zeng X, Rolle M, Shohfi J, Smith H, Ocken J, Moyer Q, Piwowarczyk P, Allington G, Dong W, van der Ent M, Chen D, Li B, Duran D, Mane S, Walcott B, Stapleton C, Aagaard-Kienitz B, Rodesch G, Jackson E, Smith E, Orbach D, Berenstein A, Bilguvar K, Zhao H, Erson-Omay Z, King P, Huttner A, Lifton R, Boggon T, Nicoli S, Jin S, Kahle K. 169 Exome Sequencing Implicates Endothelial Ras Signaling Network in Vein of Galen Aneurysmal Malformation. Neurosurgery 2023, 69: 22-22. DOI: 10.1227/neu.0000000000002375_169.Peer-Reviewed Original ResearchPathway analysisP120 Ras-GAPExome sequencingSevere vascular defectsGalen aneurysmal malformationReceptor tyrosine kinase activityTyrosine kinase activityDamaging de novoMutant embryosRas-GAPSignaling networksGenetic regulationRas activationAneurysmal malformationZebrafish modelDe novo mutationsKinase activityDisease genesAxon guidanceGenetic samplesWhole-exome sequencingHigh-output heart failureFunctional studiesCollected specimensSequencing
2022
Tandem engagement of phosphotyrosines by the dual SH2 domains of p120RasGAP
Stiegler A, Vish K, Boggon T. Tandem engagement of phosphotyrosines by the dual SH2 domains of p120RasGAP. Structure 2022, 30: 1603-1614.e5. PMID: 36417908, PMCID: PMC9722645, DOI: 10.1016/j.str.2022.10.009.Peer-Reviewed Original ResearchConceptsGTPase-activating proteinsSH2 domainSH2-SH3Src homology 2 domainDual SH2 domainsPhosphotyrosine residuesSH3 domainRho GTPasesPhosphotyrosine recognitionTarget proteinsSynergistic bindingPhosphotyrosineP120RasGAPConformational flexibilityProteinSelectivity mechanismAffinity measurementsDomainGTPasesClose proximityCassetteCrystal structureResiduesCompact arrangementBindingRho family GTPase signaling through type II p21-activated kinases
Chetty A, Ha B, Boggon T. Rho family GTPase signaling through type II p21-activated kinases. Cellular And Molecular Life Sciences 2022, 79: 598. PMID: 36401658, PMCID: PMC10105373, DOI: 10.1007/s00018-022-04618-2.Peer-Reviewed Original ResearchConceptsRho family small GTPasesP21-activated kinaseRho GTPasesSmall GTPasesPAK family membersRho family GTPaseSignal transduction pathwaysMechanism of regulationPAK familySignal transductionTransduction pathwaysGTPasesMolecular basisDownstream effectorsDomain recognitionPAKsCross talkKinasePAK groupDistinct structuresRegulationPAKFamily membersGTPaseTransductionMolecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4)
Ha B, Yigit S, Natarajan N, Morse E, Calderwood D, Boggon T. Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Communications Biology 2022, 5: 1257. PMID: 36385162, PMCID: PMC9669019, DOI: 10.1038/s42003-022-04157-3.Peer-Reviewed Original ResearchConceptsP21-activated kinase 4Integrin adhesion receptorsMolecular basisAdhesion receptorsIntegrin β5Potential cellular rolesIntegrin β tailsKinase 4Membrane-proximal halfSubstrate-binding grooveSubstrate-binding siteSite-directed mutagenesisCellular rolesPhosphoacceptor sitesΒ tailExtracellular ligandsCytoplasmic signalingCytoplasmic tailKinase domainMultiple kinasesIntegrin complexΒ5 integrinsΒ5TailMutagenesisDe novo mutations in the BMP signaling pathway in lambdoid craniosynostosis
Timberlake AT, Kiziltug E, Jin SC, Nelson-Williams C, Loring E, Allocco A, Marlier A, Banka S, Stuart H, Passos-Buenos M, Rosa R, Rogatto S, Tonne E, Stiegler A, Boggon T, Alperovich M, Steinbacher D, Staffenberg D, Flores R, Persing J, Kahle K, Lifton R. De novo mutations in the BMP signaling pathway in lambdoid craniosynostosis. Human Genetics 2022, 142: 21-32. PMID: 35997807, DOI: 10.1007/s00439-022-02477-2.Peer-Reviewed Original ResearchConceptsDe novo mutationsDamaging de novo mutationsSingle-cell RNA sequencing analysisTranscriptional co-repressorTarget sequence recognitionRNA sequencing analysisTranscription factor NfixNovo mutationsEnrichment of mutationsBMP receptorsCo-repressorParent-offspring triosTranscription factorsGenetic gainImplicating perturbationsOsteoblast precursorsPremature suture fusionSequencing analysisMolecular etiologySequence recognitionMissense mutationsMutationsExome sequencingGenetic etiologyOsteoprogenitor cells
2021
Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity
Park J, Daniels J, Wartewig T, Ringbloom KG, Martinez-Escala ME, Choi S, Thomas JJ, Doukas PG, Yang J, Snowden C, Law C, Lee Y, Lee K, Zhang Y, Conran C, Tegtmeyer K, Mo SH, Pease DR, Jothishankar B, Kwok PY, Abdulla FR, Pro B, Louissaint A, Boggon T, Sosman J, Guitart J, Rao D, Ruland J, Choi J. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood 2021, 138: 1225-1236. PMID: 34115827, PMCID: PMC8499046, DOI: 10.1182/blood.2020009655.Peer-Reviewed Original ResearchConceptsPutative driver genesDriver genesCutaneous T-cell lymphomaDisease phenotypePutative tumor suppressorT-cell lymphomaMycosis fungoidesDiverse disease phenotypesPutative genetic causesSezary syndromeDNA/RNA sequencingGenomic analysisRNA sequencingMolecular basisTumor suppressorDisease stageStructural variantsGenetic relationshipsTranscriptional signatureGenesDisease heterogeneityFunctional assaysNovel insightsSkin-homing T cellsLeukemic disease
2020
PU.1 haploinsufficiency arrests pro-B cell development
Le Coz C, Nolan B, Pillarisetti P, Khanna C, Nguyen D, Boggon T, Nicholas S, Verbsky J, Hajjar J, Poon G, Chinn I, Marson A, Romberg N. PU.1 haploinsufficiency arrests pro-B cell development. Journal Of Allergy And Clinical Immunology 2020, 145: ab344. DOI: 10.1016/j.jaci.2019.12.085.Peer-Reviewed Original Research
2019
Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis
Timberlake AT, Jin SC, Nelson-Williams C, Wu R, Furey CG, Islam B, Haider S, Loring E, Galm A, Steinbacher D, Larysz D, Staffenberg D, Flores R, Rodriguez E, Boggon T, Persing J, Lifton R, Lifton RP, Gunel M, Mane S, Bilguvar K, Gerstein M, Loring E, Nelson-Williams C, Lopez F, Knight J. Mutations in TFAP2B and previously unimplicated genes of the BMP, Wnt, and Hedgehog pathways in syndromic craniosynostosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 15116-15121. PMID: 31292255, PMCID: PMC6660739, DOI: 10.1073/pnas.1902041116.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAlpha CateninChildChild, PreschoolCraniosynostosesExomeExome SequencingFemaleGene ExpressionGlypicansHistone AcetyltransferasesHumansMaleMutationNuclear ProteinsPedigreeRisk AssessmentSignal TransductionSkullSOXC Transcription FactorsTranscription Factor AP-2Zinc Finger Protein Gli2ConceptsRare damaging mutationsSyndromic craniosynostosisCongenital anomaliesDamaging mutationsSyndromic casesExome sequencingAdditional congenital anomaliesFrequent congenital anomaliesDamaging de novo mutationsNeural crest cell migrationDamaging de novoCrest cell migrationCS patientsMutation burdenChromatin modifiersSubsequent childrenTranscription factorsDe novo mutationsCS casesCS geneHedgehog pathwayDisease locusPremature fusionFunction mutationsCraniosynostosis
2017
Skills for a scientific life
Boggon T. Skills for a scientific life. Crystallography Reviews 2017, 23: 227-229. DOI: 10.1080/0889311x.2017.1295232.Peer-Reviewed Original Research
2016
Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin
Elf S, Lin R, Xia S, Pan Y, Shan C, Wu S, Lonial S, Gaddh M, Arellano M, Khoury H, Khuri F, Lee B, Boggon T, Fan J, Chen J. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin. Oncogene 2016, 36: 254-262. PMID: 27270429, PMCID: PMC5464402, DOI: 10.1038/onc.2016.196.Peer-Reviewed Original ResearchConceptsLeukemia cellsTumor growthAntimalarial drugsNon-immune hemolytic anemiaCombined treatmentHealthy human donorsLeukemia cell viabilityXenograft nude micePrimary leukemia cellsNormal hematopoietic cellsCell viabilityHuman K562 leukemia cellsCancer cell metabolismRed blood cellsCombined therapyHemolytic anemiaAntileukemia treatmentClinical observationsNude miceHuman patientsHuman donorsAnticancer effectsK562 leukemia cellsMinimal toxicityDihydroartemisinin