2024
Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix
Bellone S, Jeong K, Halle M, Krakstad C, McNamara B, Greenman M, Mutlu L, Demirkiran C, Hartwich T, Yang-Hartwich Y, Zipponi M, Buza N, Hui P, Raspagliesi F, Lopez S, Paolini B, Milione M, Perrone E, Scambia G, Altwerger G, Ravaggi A, Bignotti E, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Quick C, Angioli R, Terranova C, Zaidi S, Nandi S, Alexandrov L, Siegel E, Choi J, Schlessinger J, Santin A. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2321898121. PMID: 38625939, PMCID: PMC11046577, DOI: 10.1073/pnas.2321898121.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingPatient-derived-xenograftsBase excision repairCopy number lossMultiregion whole-exome sequencingCopy number gainHigh-grade neuroendocrine carcinomaCNV analysisPhylogenetic analysisEvolutionary historyNeuroendocrine cervical cancerHuman papillomavirus DNAMutator phenotypeSensitivity to afatinibGenetic landscapeRecurrent mutationsRNA sequencingGene fusionsMutational landscape analysisExcision repairGenesMutationsPan-HERConsistent with deficiencyNeuroendocrine carcinoma
2015
Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain
Kobashigawa Y, Amano S, Yokogawa M, Kumeta H, Morioka H, Inouye M, Schlessinger J, Inagaki F. Structural analysis of the mechanism of phosphorylation of a critical autoregulatory tyrosine residue in FGFR1 kinase domain. Genes To Cells 2015, 20: 860-870. PMID: 26300540, DOI: 10.1111/gtc.12277.Peer-Reviewed Original ResearchConceptsFGFR1 kinase domainKinase domainFibroblast growth factor receptor 1Catalytic domainCovalent cross-linking experimentsReceptor tyrosine kinase activationNormal cellular processesSignal transduction pathwaysNonreceptor tyrosine kinaseMechanism of phosphorylationTyrosine kinase activationCross-linking experimentsInitial phosphorylation stepActivation loopCellular processesTransient dimer formationTransduction pathwaysTyrosine phosphorylationGrowth factor receptor 1Domain interactionsKinase activationMutational analysisContact sitesMolecular mechanismsTyrosine residuesExome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas
Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C, McCusker JP, Ma S, Cheng E, Straub R, Serin M, Bosenberg M, Ariyan S, Narayan D, Sznol M, Kluger HM, Mane S, Schlessinger J, Lifton RP, Halaban R. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nature Genetics 2015, 47: 996-1002. PMID: 26214590, PMCID: PMC4916843, DOI: 10.1038/ng.3361.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsBenzimidazolesDNA Mutational AnalysisDrug Resistance, NeoplasmExomeGenetic Association StudiesGenetic Predisposition to DiseaseHumansInhibitory Concentration 50Kaplan-Meier EstimateLoss of HeterozygosityMaleMelanomaMutation, MissenseNeurofibromin 1Ras ProteinsSequence Analysis, RNASkin NeoplasmsSunlightTumor Cells, CulturedFGF1 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 concentrationsFGF19Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK
Murray PB, Lax I, Reshetnyak A, Ligon GF, Lillquist JS, Natoli EJ, Shi X, Folta-Stogniew E, Gunel M, Alvarado D, Schlessinger J. Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Science Signaling 2015, 8: ra6. PMID: 25605972, DOI: 10.1126/scisignal.2005916.Peer-Reviewed Original ResearchConceptsAnaplastic lymphoma kinaseReceptor tyrosine kinasesActivation of RTKsCultured neuroblastoma cellsReceptor tyrosine kinase anaplastic lymphoma kinaseActivation of ALKStroma contributesLung adenocarcinomaLymphoma kinaseNervous systemExtracellular domainDrug resistanceNeuroblastoma cellsAberrant activationALK activityHeparinCancerPotential mechanismsGenetic amplificationActivationTyrosine kinaseAdenocarcinomaNeuroblastomaTherapyProgression
2014
Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma
Juhlin CC, Goh G, Healy JM, Fonseca AL, Scholl UI, Stenman A, Kunstman JW, Brown TC, Overton JD, Mane SM, Nelson-Williams C, Bäckdahl M, Suttorp AC, Haase M, Choi M, Schlessinger J, Rimm DL, Höög A, Prasad ML, Korah R, Larsson C, Lifton RP, Carling T. Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma. The Journal Of Clinical Endocrinology & Metabolism 2014, 100: e493-e502. PMID: 25490274, PMCID: PMC5393505, DOI: 10.1210/jc.2014-3282.Peer-Reviewed Original ResearchConceptsAdrenocortical carcinomaSomatic mutationsCopy number alterationsNumber alterationsNonsynonymous somatic mutationsWnt pathway dysregulationHomozygous deletionMajority of casesPotential disease-causing mutationsWhole-exome sequencingUnderlying somatic mutationsLethal malignancyPathway dysregulationTumorsExome sequencingFocal CNAsDisease-causing mutationsCarcinomaTERT locusZNRF3Recurrent CNAsAlterationsNormal samplesTP53Unknown roleThe docking protein FRS2α is a critical regulator of VEGF receptors signaling
Chen PY, Qin L, Zhuang ZW, Tellides G, Lax I, Schlessinger J, Simons M. The docking protein FRS2α is a critical regulator of VEGF receptors signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 5514-5519. PMID: 24706887, PMCID: PMC3992672, DOI: 10.1073/pnas.1404545111.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCell MovementDNA PrimersEndothelial CellsGene Expression ProfilingGenetic VectorsHEK293 CellsHuman Umbilical Vein Endothelial CellsHumansImmunoblottingImmunohistochemistryImmunoprecipitationLaser-Doppler FlowmetryLentivirusMembrane ProteinsMiceReal-Time Polymerase Chain ReactionReceptors, Vascular Endothelial Growth FactorSignal TransductionX-Ray MicrotomographyConceptsLymphatic endothelial cell migrationFibroblast growth factor receptor substrate 2Growth factor receptor substrate 2Cognate receptor tyrosine kinasesFactor receptor substrate 2Receptor kinase signalingVascular endothelial growth factorPostnatal vascular developmentReceptor tyrosine kinasesEndothelial cell migrationKinase signalingEndothelial-specific deletionAdult angiogenesisVEGF receptorsTyrosine kinaseCritical regulatorVascular developmentFRS2αSubstrate 2Cell migrationDependent activationCritical roleUnidentified componentsGrowth factorEndothelial growth factorReceptor Tyrosine Kinases: Legacy of the First Two Decades
Schlessinger J. Receptor Tyrosine Kinases: Legacy of the First Two Decades. Cold Spring Harbor Perspectives In Biology 2014, 6: a008912. PMID: 24591517, PMCID: PMC3949355, DOI: 10.1101/cshperspect.a008912.Peer-Reviewed Original ResearchStructure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers
Opatowsky Y, Lax I, Tomé F, Bleichert F, Unger VM, Schlessinger J. Structure, domain organization, and different conformational states of stem cell factor-induced intact KIT dimers. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 1772-1777. PMID: 24449920, PMCID: PMC3918759, DOI: 10.1073/pnas.1323254111.Peer-Reviewed Original ResearchConceptsExtracellular regionConformational statesIg-like domainsReceptor tyrosine kinasesDifferent conformational statesTrans autophosphorylationTyrosine kinase domainMembrane-proximal Ig-like domainsTrans phosphorylationAutophosphorylation sitesDomain organizationKinase domainCytoplasmic regionHomotypic interactionsKinase activityReceptor dimersDimeric receptorTyrosine kinaseAsymmetric arrangementMolecular interactionsPrevalent conformationsCrystal structureAutophosphorylationDimersKinaseDifferential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivities
Lew ED, Oh J, Burrola PG, Lax I, Zagórska A, Través PG, Schlessinger J, Lemke G. Differential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivities. ELife 2014, 3: e03385. PMID: 25265470, PMCID: PMC4206827, DOI: 10.7554/elife.03385.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxl Receptor Tyrosine KinaseBone Marrow CellsC-Mer Tyrosine KinaseCell LineEmbryo, MammalianFemaleFibroblastsGene Expression RegulationHEK293 CellsHumansIntercellular Signaling Peptides and ProteinsMaleMiceMice, Inbred C57BLMice, KnockoutPhagocytosisPhosphatidylserinesPrimary Cell CultureProtein SProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesRecombinant ProteinsSignal TransductionConceptsActivation of MerWild-type affinityReceptor tyrosine kinasesCellular physiologyReceptor-ligand engagementTAM receptor tyrosine kinasesGenetic analysisLigand specificityTyrosine kinaseLigand engagementPhospholipid phosphatidylserineGla domainPhospholipid interactionsDifferential activityProtein SAxlGas6PhosphatidylserinePhagocytosisPredominant roleKinasePhysiologyRegulationActivationReceptors
2013
Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region
Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, Schlessinger J. Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 17832-17837. PMID: 24127596, PMCID: PMC3816449, DOI: 10.1073/pnas.1317118110.Peer-Reviewed Original ResearchConceptsKIT antibodyReceptor tyrosine kinase inhibitionGastrointestinal stromal tumorsAcute myeloid leukemiaDurable disease controlTyrosine kinase inhibitorsTyrosine kinase inhibitionSomatic oncogenic mutationsUnique therapeutic approachClinical progressionStromal tumorsMyeloid leukemiaTherapeutic approachesDramatic responseTreatment of KITDrug resistanceDisease controlIsolated antibodyKIT inhibitionKinase inhibitorsAntibodiesCancerCell proliferationOncogenic mutationsKinase inhibitionLandscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma
Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, Guzzo F, English DP, Varughese J, Gasparrini S, Bortolomai I, Buza N, Hui P, Abu-Khalaf M, Ravaggi A, Bignotti E, Bandiera E, Romani C, Todeschini P, Tassi R, Zanotti L, Carrara L, Pecorelli S, Silasi DA, Ratner E, Azodi M, Schwartz PE, Rutherford TJ, Stiegler AL, Mane S, Boggon TJ, Schlessinger J, Lifton RP, Santin AD. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 2916-2921. PMID: 23359684, PMCID: PMC3581983, DOI: 10.1073/pnas.1222577110.Peer-Reviewed Original ResearchConceptsNuRD chromatin-remodeling complexSomatic copy number variationsSomatic mutationsCell proliferation pathwaysCopy number mutationsDNA mismatch repairCopy number variationsCopy number lossChromatin remodelingTranscriptional machineryCopy number gainsChromosome segmentsFrequent mutationsChromosome 19Loss of TP53Cell cycleCancer genesWhole-exome sequencingBurden of mutationsMismatch repairProliferation pathwaysDNA damageMutational landscapeNormal DNAFrequent amplificationRAC1P29S is a spontaneously activating cancer-associated GTPase
Davis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ. RAC1P29S is a spontaneously activating cancer-associated GTPase. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 912-917. PMID: 23284172, PMCID: PMC3549122, DOI: 10.1073/pnas.1220895110.Peer-Reviewed Original ResearchAmino Acid SubstitutionAnimalsCell Surface ExtensionsChlorocebus aethiopsCOS CellsCrystallography, X-RayEnzyme ActivationGenetic Association StudiesGuanosine TriphosphateHumansHydrolysisKineticsMelanomaMiceMicroscopy, FluorescenceModels, MolecularMutation, MissenseNIH 3T3 CellsOncogenesRac1 GTP-Binding ProteinRecombinant Fusion ProteinsSignal TransductionStatic Electricity
2010
Cell Signaling by Receptor Tyrosine Kinases
Lemmon MA, Schlessinger J. Cell Signaling by Receptor Tyrosine Kinases. Cell 2010, 141: 1117-1134. PMID: 20602996, PMCID: PMC2914105, DOI: 10.1016/j.cell.2010.06.011.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesTyrosine kinaseIntracellular tyrosine kinase domainRecent structural studiesGrowth factor ligandsTyrosine kinase domainUnexpected diversityKinase domainCell signalingLigand bindingCellular responsesFactor ligandRTK mutationsKinaseStructural studiesActivationSignalingDiversityMutationsDimerizationMechanismBindingDomainAsymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells
Bae JH, Boggon TJ, Tomé F, Mandiyan V, Lax I, Schlessinger J. Asymmetric receptor contact is required for tyrosine autophosphorylation of fibroblast growth factor receptor in living cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 2866-2871. PMID: 20133753, PMCID: PMC2840318, DOI: 10.1073/pnas.0914157107.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesTyrosine autophosphorylationKinase moleculesTyrosine kinaseFGFR1 kinase domainSpecific docking sitesAsymmetric dimer formationFibroblast growth factor receptorActivation of intracellularKinase domainOncogenic activating mutationsGrowth factor receptorMolecular basisDocking siteKinase activityBiochemical experimentsActive enzymeN-lobeC-lobeFGF receptorsFunction mutationsAutophosphorylationTransphosphorylationLiving cellsFactor receptor
2009
The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site
Bae JH, Lew ED, Yuzawa S, Tomé F, Lax I, Schlessinger J. The Selectivity of Receptor Tyrosine Kinase Signaling Is Controlled by a Secondary SH2 Domain Binding Site. Cell 2009, 138: 514-524. PMID: 19665973, PMCID: PMC4764080, DOI: 10.1016/j.cell.2009.05.028.Peer-Reviewed Original ResearchConceptsSH2 domainSH2 domain-mediated interactionsReceptor tyrosine kinase signalingPhosphorylation-independent mannerReceptor phosphorylation sitesDomain-mediated interactionsDomain Binding SiteSpecific cellular processesTyrosine kinase signalingParticular sequence motifsReceptor tyrosine kinasesBinding sitesTyrosine kinase domainPhosphorylation sitesCellular processesSequence motifsPhospholipase CgammaKinase signalingKinase domainTyrosine kinaseSecondary binding siteCultured cellsDomain selectivityRegulation of selectivityIndependent manner
2007
Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation
Lew ED, Bae JH, Rohmann E, Wollnik B, Schlessinger J. Structural basis for reduced FGFR2 activity in LADD syndrome: Implications for FGFR autoinhibition and activation. Proceedings Of The National Academy Of Sciences Of The United States Of America 2007, 104: 19802-19807. PMID: 18056630, PMCID: PMC2148379, DOI: 10.1073/pnas.0709905104.Peer-Reviewed Original ResearchMeSH KeywordsAbnormalities, MultipleAdenosine TriphosphateAlanineCrystallography, X-RayHumansModels, MolecularMutationPhosphorylationProtein BindingProtein Structure, TertiaryReceptor, Fibroblast Growth Factor, Type 1Receptor, Fibroblast Growth Factor, Type 2Structural Homology, ProteinSubstrate SpecificitySyndromeConceptsFibroblast growth factor receptor 2Tyrosine kinase activityKinase activityStatic crystallographic snapshotsKinase hinge regionSevere skeletal disorderTyrosine kinase domainAutophosphorylation kineticsFGFR2 kinaseFGFR1 kinaseKinase domainKey residuesStructural basisMutation altersFGFR2 activityConformational dynamicsCrystallographic snapshotsStringent modeCatalytic pocketFGF receptorsFunction mutationsKinaseMultiple gainsMissense mutationsAutoinhibitionStructural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor
Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural Basis for Activation of the Receptor Tyrosine Kinase KIT by Stem Cell Factor. Cell 2007, 130: 323-334. PMID: 17662946, DOI: 10.1016/j.cell.2007.05.055.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceBinding SitesCrystallography, X-RayDimerizationDiseaseEnzyme ActivationHumansLigandsModels, MolecularMolecular Sequence DataMutationProtein BindingProtein Structure, SecondaryProtein Structure, TertiaryProto-Oncogene Proteins c-kitStem Cell FactorStructure-Activity RelationshipConceptsStem cell factorReceptor dimerizationLigand-induced receptor dimerizationCell factorMultiple cellular responsesTyrosine kinase activationReceptor tyrosine kinase KITKIT dimerizationTyrosine kinase KITDomain D4Structural basisCritical residuesKinase activationSCF stimulationCellular responsesConformational changesOncogenic mutationsCultured cellsAmino acidsPoint mutationsKIT activationEntire ectodomainKinase KITKey hallmarksSole role
1992
Differential Effects of Carboxy-Terminal Sequence Deletions on Platelet-Derived Growth Factor Receptor Signaling Activities and Interactions with Cellular Substrates
Seedorf K, Millauer B, Kostka G, Schlessinger J, Ullrich A. Differential Effects of Carboxy-Terminal Sequence Deletions on Platelet-Derived Growth Factor Receptor Signaling Activities and Interactions with Cellular Substrates. Molecular And Cellular Biology 1992, 12: 4347-4356. DOI: 10.1128/mcb.12.10.4347-4356.1992.Peer-Reviewed Original ResearchNIH 3T3 cellsRas GTPase-activating proteinCarboxy-terminal amino acidsSignaling pathwayGTPase-activating proteinSignaling activityAmino acidsWild-type levelsPDGF-RSubstrates in vitroC-terminal truncationEGF-RReceptor signaling activityMitogenic activityPhosphotidylinositol 3-kinaseWild-type receptorBiological signaling activitiesSequence deletionsSubstrate phosphorylationCellular polypeptidesCellular proteinsCytoplasmic domainIntracellular sequencesSignaling potentialExtracellular domain
1991
A Dominant Negative Mutation Suppresses the Function of Normal Epidermal Growth Factor Receptors by Heterodimerization
Kashles O, Yarden Y, Fischer R, Ullrich A, Schlessinger J. A Dominant Negative Mutation Suppresses the Function of Normal Epidermal Growth Factor Receptors by Heterodimerization. Molecular And Cellular Biology 1991, 11: 1454-1463. DOI: 10.1128/mcb.11.3.1454-1463.1991.Peer-Reviewed Original ResearchDominant negative mutationWild-type receptorEpidermal growth factorNegative mutationMutant receptorsWild-type EGF receptorEGF receptorResponse to EGFInactive deletion mutantsCovalent cross-linking experimentsLiving cellsWild-typeEpidermal growth factor receptorRate of receptor endocytosisCross-linking experimentsDeletion mutantsTyrosine autophosphorylationCytoplasmic domainCells expressing wild-type receptorsReceptor endocytosisMurine embryogenesisKinase activityHigh-affinity binding sitesReceptor dimerizationNormal receptors