2024
Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation
Trogdon M, Abbott K, Arang N, Lande K, Kaur N, Tong M, Bakhoum M, Gutkind J, Stites E. Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation. Npj Systems Biology And Applications 2024, 10: 75. PMID: 39013872, PMCID: PMC11252164, DOI: 10.1038/s41540-024-00400-1.Peer-Reviewed Original ResearchMeSH KeywordsGTP-Binding ProteinsHumansMelanomaModels, BiologicalMutationReceptors, G-Protein-CoupledSignal TransductionSystems BiologyUveal NeoplasmsConceptsSignaling networksMathematical models of biochemical reaction networksModels of biochemical reaction networksG-proteinCell signaling networksDisease-causing mutationsComputational systems biologyBiochemical reaction networksDownstream pathway activationSignaling phenotypeSystems biologyBioinformatics analysisGPCR signalingMutationsCo-occurring mutationsOncogenic mutationsPathway activationDiscovery toolPathwayReaction networkSignalCYSLTR2 mutationsDiscoveryPhenotypeMutually-exclusive
2023
Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation
Mendiratta G, Stites E. Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation. ELife 2023, 12: e82739. PMID: 37823369, PMCID: PMC10627510, DOI: 10.7554/elife.82739.Peer-Reviewed Original ResearchComputational Random Mutagenesis to Investigate RAS Mutant Signaling
Stites E. Computational Random Mutagenesis to Investigate RAS Mutant Signaling. Methods In Molecular Biology 2023, 2634: 329-335. PMID: 37074586, PMCID: PMC10530643, DOI: 10.1007/978-1-0716-3008-2_15.Peer-Reviewed Original Research
2019
A systems mechanism for KRAS mutant allele–specific responses to targeted therapy
McFall T, Diedrich J, Mengistu M, Littlechild S, Paskvan K, Sisk-Hackworth L, Moresco J, Shaw A, Stites E. A systems mechanism for KRAS mutant allele–specific responses to targeted therapy. Science Signaling 2019, 12 PMID: 31551296, PMCID: PMC6864030, DOI: 10.1126/scisignal.aaw8288.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorWild-type Ras activationColorectal cancerSensitivity to EGFR inhibitionEpidermal growth factor receptor inhibitionKRAS mutantEGFR-independent mannerAllele-specific responsesRas activationGrowth factor receptorTumor suppressor neurofibrominPatient tumorsAntibody cetuximabTargeted therapyMechanisms of EGFR signalingCRC patientsEGFR inhibitionCancer treatment decisionsRAS mutationsFactor receptorKRASTherapeutic strategiesTreatment decisionsEGFR signalingPatientsModeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor
Erickson KE, Rukhlenko OS, Shahinuzzaman M, Slavkova KP, Lin YT, Suderman R, Stites EC, Anghel M, Posner RG, Barua D, Kholodenko BN, Hlavacek WS. Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor. PLOS Computational Biology 2019, 15: e1006706. PMID: 30653502, PMCID: PMC6353226, DOI: 10.1371/journal.pcbi.1006706.Peer-Reviewed Original ResearchConceptsReceptor tyrosine kinasesSrc homology 2Autophosphorylation sitesInsulin-like growth factor 1 receptorGrowth factor 1 receptorFactor 1 receptorPTB domain-containing proteinsCopy numberDomain-containing proteinsPhosphotyrosine-binding (PTB) domainProtein copy numbersMultiple autophosphorylation sitesProtein abundance profilesMultiple signaling proteinsShort linear motifsOutcome of competitionCell line-specific modelsHomology 2Cytoplasmic domainSignaling proteinsLinear motifsTyrosine kinaseEffects of competitionRule-based modeling approachRelative abundance
2018
Proceedings of the fifth international RASopathies symposium: When development and cancer intersect
Rauen K, Schoyer L, Schill L, Stronach B, Albeck J, Andresen B, Cavé H, Ellis M, Fruchtman S, Gelb B, Gibson C, Gripp K, Hefner E, Huang W, Itkin M, Kerr B, Linardic C, McMahon M, Oberlander B, Perlstein E, Ratner N, Rogers L, Schenck A, Shankar S, Shvartsman S, Stevenson D, Stites E, Stork P, Sun C, Therrien M, Ullian E, Widemann B, Yeh E, Zampino G, Zenker M, Timmer W, McCormick F. Proceedings of the fifth international RASopathies symposium: When development and cancer intersect. American Journal Of Medical Genetics Part A 2018, 176: 2924-2929. PMID: 30302932, PMCID: PMC6312476, DOI: 10.1002/ajmg.a.40632.Peer-Reviewed Original ResearchConceptsGerm line mutationsPredisposition to cancerSomatic malignancyOcular abnormalitiesCraniofacial dysmorphologyMalformation syndromePathogenetic etiologyRas/mitogen-activated protein kinasePathogenetic mechanismsEffects of dysregulationSomatic cancersOncogenic pathwaysCancerPhenotypic featuresRASopathiesMAPK pathwayRas pathwayNormal functionEncode componentsProtein kinaseNeurocognitive issuesExcellent modelPathwayMalignancyQuantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors
Stites E, Shaw A. Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors. CPT Pharmacometrics & Systems Pharmacology 2018, 7: 342-351. PMID: 29484842, PMCID: PMC5980551, DOI: 10.1002/psp4.12291.Peer-Reviewed Original ResearchConceptsRegulates Ras activitySystems biology approachBiology approachRas activationProtein turnoverKRAS-G12C covalent inhibitorsKRAS G12C inhibitorsSystems pharmacology analysisRasKRAS mutantDrug developmentG12C inhibitorsCovalent inhibitorsInhibitorsKRASMutantsPharmacological analysisMutationsKRAS G12C
2015
Use of Mechanistic Models to Integrate and Analyze Multiple Proteomic Datasets
Stites E, Aziz M, Creamer M, Von Hoff D, Posner R, Hlavacek W. Use of Mechanistic Models to Integrate and Analyze Multiple Proteomic Datasets. Biophysical Journal 2015, 108: 1819-1829. PMID: 25863072, PMCID: PMC4390817, DOI: 10.1016/j.bpj.2015.02.030.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorExperimentally detected interactionsPhosphotyrosine-binding domainSrc homology 2Recruitment of proteinsCell line-specific modelsProtein copy numbersProtein-protein interactionsCell signaling networksEpidermal growth factor receptor signalingCell linesWell-characterized roleCell line-specific differencesLow-affinity interactionsLine-specific differencesActivation of EGFR signalingMultiple cell linesLigand-stimulated activationAutophosphorylation sitesSignaling networksProteomic datasetsCopy numberHomolog 2EGFR signalingMap interactions
2013
Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine
Stites E. Chemical kinetic mechanistic models to investigate cancer biology and impact cancer medicine. Physical Biology 2013, 10: 026004. PMID: 23406820, DOI: 10.1088/1478-3975/10/2/026004.Peer-Reviewed Original ResearchMeSH KeywordsComputer SimulationHumansModels, BiologicalMutationNeoplasmsSignal TransductionSystems BiologyConceptsBiochemical networksCancer biologyInvestigate cancer biologyDisrupt cellular processesAcquisition of mutationsCellular processesClinical management of cancer patientsMutated genesCancer medicineMolecular biologyExperimental biologyFeatures of cancerBiologyMutationsMechanistic modelExperimental approachGenesMolecular reactionsPace of progressKinetic mechanistic modelsCancerManagement of cancer patients
2012
Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling
Creamer M, Stites E, Aziz M, Cahill J, Tan C, Berens M, Han H, Bussey K, Von Hoff D, Hlavacek W, Posner R. Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling. BMC Systems Biology 2012, 6: 107. PMID: 22913808, PMCID: PMC3485121, DOI: 10.1186/1752-0509-6-107.Peer-Reviewed Original ResearchMeSH KeywordsComputational BiologyComputer GraphicsModels, BiologicalReceptor Protein-Tyrosine KinasesSignal TransductionConceptsCell signaling networksSignaling networksErbB receptor signalingRule-based modeling approachSignaling proteinsPost-translational modification stateSites of post-translational modificationsNetwork-free simulationCellular signaling networksProtein-protein interactionsPost-translational modificationsReceptor signalingSite of modificationActivation of ERKModification statesProtein complexesProtein interactionsContact mapsCellular signalingTyrosine residuesIndividual serinesDevelopment of softwareProteinRule-based modelKinetics of molecular interactionsMathematical Investigation of How Oncogenic Ras Mutants Promote Ras Signaling
Stites E, Ravichandran K. Mathematical Investigation of How Oncogenic Ras Mutants Promote Ras Signaling. Methods In Molecular Biology 2012, 880: 69-85. PMID: 23361982, DOI: 10.1007/978-1-61779-833-7_5.Peer-Reviewed Original ResearchMeSH KeywordsComputational BiologyGenes, rasHumansKineticsModels, GeneticMutationRas ProteinsSignal TransductionStatistics as Topic
2011
Mechanistic modeling to investigate signaling by oncogenic Ras mutants
Stites E, Ravichandran K. Mechanistic modeling to investigate signaling by oncogenic Ras mutants. WIREs Mechanisms Of Disease 2011, 4: 117-127. PMID: 21766467, DOI: 10.1002/wsbm.156.Peer-Reviewed Original ResearchMeSH KeywordsCell CommunicationHumansModels, GeneticMutationNeoplasmsOncogenesRas ProteinsSignal TransductionConceptsCell signaling networksSignaling networksCancer phenotypeMutant Ras signalingAcquisition of mutationsRas signalingCell signalingBiochemistry of proteinsLevel of signalMutated genesExpression levelsBiochemical reaction mechanismsPhenotypeMechanistic modelInvestigated signalSignalGenesMutationsRasProteinCancerIndividual reactionsExpression
2010
Modeling Membrane Localization: Case Study of a Ras Signaling Model
Stites E. Modeling Membrane Localization: Case Study of a Ras Signaling Model. Advances In Experimental Medicine And Biology 2010, 680: 661-667. PMID: 20865552, DOI: 10.1007/978-1-4419-5913-3_73.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell MembraneComputational BiologyHumansMembrane ProteinsModels, BiologicalMutant ProteinsRas ProteinsSignal TransductionTransfection
2009
A Systems Perspective of Ras Signaling in Cancer
Stites E, Ravichandran K. A Systems Perspective of Ras Signaling in Cancer. Clinical Cancer Research 2009, 15: 1510-1513. PMID: 19208795, DOI: 10.1158/1078-0432.ccr-08-2753.Peer-Reviewed Original Research
2007
Network Analysis of Oncogenic Ras Activation in Cancer
Stites E, Trampont P, Ma Z, Ravichandran K. Network Analysis of Oncogenic Ras Activation in Cancer. Science 2007, 318: 463-467. PMID: 17947584, DOI: 10.1126/science.1144642.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsCell LineCell Line, TumorCell Transformation, NeoplasticComputer SimulationExtracellular Signal-Regulated MAP KinasesGenes, rasGTP PhosphohydrolasesGTPase-Activating ProteinsGuanosine DiphosphateGuanosine TriphosphateHumansMathematicsMetabolic Networks and PathwaysModels, BiologicalNeoplasmsPhosphorylationPoint MutationRas ProteinsSignal Transduction