Featured Publications
Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma
Tworkoski K, Singhal G, Szpakowski S, Zito CI, Bacchiocchi A, Muthusamy V, Bosenberg M, Krauthammer M, Halaban R, Stern DF. Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma. Molecular Cancer Research 2011, 9: 801-812. PMID: 21521745, PMCID: PMC3117976, DOI: 10.1158/1541-7786.mcr-10-0512.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisCell Line, TumorCell MovementCell ProliferationErbB ReceptorsGene Expression Regulation, NeoplasticGene Knockdown TechniquesHEK293 CellsHumansInfant, NewbornMelanocytesMelanomaPhosphoproteinsPhosphorylationProteomicsReceptor Protein-Tyrosine KinasesReceptor, IGF Type 2RNA, Small InterferingSignal TransductionSkin NeoplasmsSTAT3 Transcription FactorConceptsTherapeutic targetReceptor tyrosine kinasesMelanoma cellsPotential therapeutic targetIdentifies potential therapeutic targetsActive receptor tyrosine kinasesTyrosine kinaseMelanoma cell migrationReceptor expressionBreast cancerAxl knockdownAutocrine circuitTherapeutic interventionsCancer subtypesReceptor tyrosine kinase activationTyrosine kinase activationNovel targetActivated receptorsAxlRNA knockdownMelanomaCell migrationHER3KnockdownIGF1RNFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways*
Xu X, Stern DF. NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways*. Journal Of Biological Chemistry 2002, 278: 8795-8803. PMID: 12499369, DOI: 10.1074/jbc.m211392200.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAmino Acid SequenceBase SequenceCell Cycle ProteinsChromatinDNA DamageDNA PrimersDNA ReplicationDNA-Binding ProteinsFluorescent Antibody Technique, IndirectG2 PhaseHeLa CellsHumansMitosisMolecular Sequence DataNuclear ProteinsPhosphorylationSequence Homology, Amino AcidSignal TransductionTrans-ActivatorsConceptsN-terminal FHA domainChromatin-associated proteinsDNA damageDNA Damage Signaling PathwayDNA double-strand breaksDiscrete nuclear fociDNA damage responseNumber of proteinsDouble-strand breaksBRCT domainFHA domainGamma-H2AX fociNuclear fociRad50 fociDamage responseDNA repairNFBD1Signaling pathwaysTandem repeatsProteinNuclear factorUntreated cellsHydroxyurea treatmentPathwayDiffuse nuclear stainingSpecificity within the EGF family/ErbB receptor family signaling network
Riese D, Stern D. Specificity within the EGF family/ErbB receptor family signaling network. BioEssays 1998, 20: 41-48. PMID: 9504046, DOI: 10.1002/(sici)1521-1878(199801)20:1<41::aid-bies7>3.0.co;2-v.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesEpidermal Growth FactorHumansOncogene Proteins v-erbBSignal TransductionConceptsErbB family receptorsFamily receptorsEpidermal growth factor (EGF) familyErbB receptor familyGrowth factor familyPeptide growth factorsReceptor couplingHormone-receptor interactionBiological responsesGrowth factorHormoneMultiple receptorsReceptorsReceptor familyCell proliferationErbB familyMultiple hormonesReceptor partnersTyrosine kinaseDiverse biological responsesActivation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor.
DiGiovanna MP, Stern DF. Activation state-specific monoclonal antibody detects tyrosine phosphorylated p185neu/erbB-2 in a subset of human breast tumors overexpressing this receptor. Cancer Research 1995, 55: 1946-55. PMID: 7728765.Peer-Reviewed Original ResearchConceptsHuman breast tumorsBreast tumorsPrimary human breast tumorsPoor patient prognosisSubset of tumorsEpidermal growth factor receptorGrowth factor receptorPatient prognosisImmunohistochemical stainingNeu/ErbBTumor samplesTumorsMonoclonal antibodiesHuman tumorsFactor receptorRelated receptorsReceptorsP185Polyclonal antibodiesAntibodiesErbBRelated epidermal growth factor receptorSubsetTyrosine phosphoproteinsPrognosisThe Cellular Response to Neuregulins Is Governed by Complex Interactions of the erbB Receptor Family
Riese D, van Raaij T, Plowman G, Andrews G, Stern D. The Cellular Response to Neuregulins Is Governed by Complex Interactions of the erbB Receptor Family. Molecular And Cellular Biology 1995, 15: 5770-5776. PMID: 7565730, PMCID: PMC230829, DOI: 10.1128/mcb.15.10.5770.Peer-Reviewed Original ResearchConceptsReceptor familyEpidermal growth factor receptor tyrosine kinase familyErbB family receptorsErbB receptor familyReceptor tyrosine kinase familyReceptor tyrosine phosphorylationPeptide agonistsFamily receptorsTyrosine kinase familyHuman cancersReceptor interactionEpidermal growth factor homology domainsCell linesCell survivalReceptorsNeuregulinCellular responsesTyrosine phosphorylation
2018
Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer
Theodosakis N, Langdon CG, Micevic G, Krykbaeva I, Means RE, Stern DF, Bosenberg MW. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment‐resistant melanoma, colorectal, and lung cancer. Pigment Cell & Melanoma Research 2018, 32: 292-302. PMID: 30281931, PMCID: PMC6590911, DOI: 10.1111/pcmr.12742.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationColorectal NeoplasmsDrug Resistance, NeoplasmDrug SynergismHumansHydroxymethylglutaryl-CoA Reductase InhibitorsLung NeoplasmsMaleMelanomaMevalonic AcidMice, NudeMitogen-Activated Protein KinasesPrenylationProtein Kinase InhibitorsProtein Processing, Post-TranslationalSignal TransductionConceptsUseful adjunctive therapyHMG-CoA reductase inhibitorsAnti-tumor effectsAdjunctive therapyInhibition of isoprenylationLung cancerMEK inhibitionReductase inhibitorsMAPK blockadeDriver mutationsAdditional studiesStatinsTherapyMelanomaTumorsVemurafenibMAPK pathwayDownstream metabolitesInhibitionMAPKAdjunctiveColorectalSelumetinibBlockadeCancerKeeping Tumors Out of the MAPK Fitness Zone
Stern DF. Keeping Tumors Out of the MAPK Fitness Zone. Cancer Discovery 2018, 8: 20-23. PMID: 29311225, DOI: 10.1158/2159-8290.cd-17-1243.Peer-Reviewed Original ResearchMeSH KeywordsCell DeathCell Line, TumorHumansMAP Kinase Signaling SystemProtein Kinase InhibitorsProto-Oncogene Proteins B-rafSignal TransductionConceptsMAPK-targeted therapiesGreater fitnessMAPK signalingTumor cell subclonesMAPK pathwayCell deathERK inhibitorDNA damageTumor cell deathFitness barriersCell subclonesNew therapeutic approachesInhibitor withdrawalResistant clonesTherapeutic approachesTriple combinationMEKSignalingClonesSubclonesFitnessPathwayPatients
2017
p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis
Theodosakis N, Micevic G, Langdon CG, Ventura A, Means R, Stern DF, Bosenberg MW. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. Journal Of Investigative Dermatology 2017, 137: 2187-2196. PMID: 28599981, PMCID: PMC6342201, DOI: 10.1016/j.jid.2016.12.033.Peer-Reviewed Original ResearchConceptsProtein synthesisRibosomal S6 kinase (RSK) familyPatient-derived melanoma cell linesDifferential protein expressionReverse phase protein arrayPhase protein arrayTranslation complexesKinase familyBI-D1870RSK inhibitorsMelanoma cell linesProtein arraysCell proliferationInhibitor treatmentProtein expressionCell linesNew targetsHuman melanoma patientsBRAF inhibitor vemurafenib
2016
PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer
Jeong J, VanHouten JN, Dann P, Kim W, Sullivan C, Yu H, Liotta L, Espina V, Stern DF, Friedman PA, Wysolmerski JJ. PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e282-e290. PMID: 26729871, PMCID: PMC4725473, DOI: 10.1073/pnas.1516138113.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCalciumCarcinogenesisCell Line, TumorCell MembraneCell ProliferationCell SurvivalEndocytosisFemaleFluorescent Antibody TechniqueForkhead Box Protein O1Forkhead Transcription FactorsGene Knockdown TechniquesHSP90 Heat-Shock ProteinsHumansImmunoblottingIntracellular SpaceMammary Neoplasms, AnimalMicePlasma Membrane Calcium-Transporting ATPasesProtein BindingProtein TransportReceptor, ErbB-2Signal TransductionSurvival AnalysisConceptsBreast cancerHigh tumor levelsDegradation of HER2Increases Intracellular CalciumMouse mammary tumor virusBreast cancer cellsMammary tumor virusPMCA2 levelsNeu miceTumor levelsFormation of tumorsHER2 levelsIntracellular calciumTherapeutic targetBreast tumorsHER2Milk calciumExpression correlatesCancerHSP 90Mammary glandCancer cellsTumor virusTumorsCalcium
2015
SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells
Langdon CG, Wiedemann N, Held MA, Mamillapalli R, Iyidogan P, Theodosakis N, Platt JT, Levy F, Vuagniaux G, Wang S, Bosenberg MW, Stern DF. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells. Oncotarget 2015, 6: 37410-37425. PMID: 26485762, PMCID: PMC4741938, DOI: 10.18632/oncotarget.6138.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma of LungAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisApoptosis Regulatory ProteinsAzepinesAzocinesBenzhydryl CompoundsCamptothecinCell Line, TumorCell ProliferationDocetaxelDose-Response Relationship, DrugDrug SynergismFemaleHumansIrinotecanLung NeoplasmsMice, Inbred BALB CMice, NudeNF-kappa BPaclitaxelSignal TransductionTaxoidsTime FactorsTopoisomerase InhibitorsTriazolesTumor BurdenXenograft Model Antitumor AssaysConceptsLung adenocarcinoma cellsDebio 1143Adenocarcinoma cellsOngoing clinical trialsNon-canonical NF-κB signalingTopoisomerase inhibitorsLung adenocarcinoma xenograftsNF-κB signalingBromodomain inhibitor JQ1Clinical trialsConventional chemotherapyTumor volumeVivo treatmentAdenocarcinoma xenograftsAnti-apoptotic proteinsSingle agentCaspase-8 expressionVivo growthInhibitor JQ1Tumor cellsPro-apoptotic protein SmacJQ1Cell linesInhibitorsTaxanesThe broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors
Langdon CG, Held MA, Platt JT, Meeth K, Iyidogan P, Mamillapalli R, Koo AB, Klein M, Liu Z, Bosenberg MW, Stern DF. The broad‐spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF‐mutant melanoma cells in combination with other signaling pathway inhibitors. Pigment Cell & Melanoma Research 2015, 28: 417-430. PMID: 25854919, PMCID: PMC5215495, DOI: 10.1111/pcmr.12376.Peer-Reviewed Original ResearchConceptsBRAF-mutant melanomaBRAF inhibitorsCell linesCombination of dovitinibBRAF inhibitor treatmentBRAF mutant melanoma cellsBRAF inhibitor resistanceColorectal carcinoma cell linesBRAF-mutant melanoma cell linesMelanoma cell linesCarcinoma cell linesMetastatic melanomaEffective therapyWild-type BRAF cellsInhibitor treatmentAgent inhibitsPathway inhibitorDovitinibInhibitor resistanceMelanoma cellsMelanomaSecond agentInhibitorsTreatment
2014
Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells
Wali VB, Haskins JW, Gilmore-Hebert M, Platt JT, Liu Z, Stern DF. Convergent and Divergent Cellular Responses by ErbB4 Isoforms in Mammary Epithelial Cells. Molecular Cancer Research 2014, 12: 1140-1155. PMID: 24829397, PMCID: PMC4728083, DOI: 10.1158/1541-7786.mcr-13-0637.Peer-Reviewed Original ResearchConceptsYAP/Hippo pathwayIsogenic MCF10A cellsMultiple structural isoformsAlternative mRNA splicingDivergent cellular responsesChIP-seq experimentsProteases/protease inhibitorsErbB4 isoformsMammary epithelial cellsAssociation of ErbB4Hippo pathwayMRNA splicingNovel molecular targetsTranscriptional profilingDivergent functionsTranscription factorsCYT-1Signaling activitiesMevalonate pathwayCellular responsesLuminal breast cancer cell linesDiverse biologic activitiesMCF10A cellsCYT-2Intracellular isoformsSignificance of glioma-associated oncogene homolog 1 (GLI1)expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway
Colavito SA, Zou MR, Yan Q, Nguyen DX, Stern DF. Significance of glioma-associated oncogene homolog 1 (GLI1)expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway. Breast Cancer Research 2014, 16: 444. PMID: 25252859, PMCID: PMC4303124, DOI: 10.1186/s13058-014-0444-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsBreast NeoplasmsCell Line, TumorCell MovementCell ProliferationClaudinsEpithelial-Mesenchymal TransitionFemaleGene ExpressionHeterocyclic Compounds, 2-RingHumansMice, Inbred NODMice, SCIDNeoplasm TransplantationNeoplastic Stem CellsNF-kappa BPromoter Regions, GeneticProtein BindingReceptor Cross-TalkRNA, MessengerSignal TransductionThiazolesTranscription FactorsZinc Finger Protein GLI1ConceptsGlioma-associated oncogene homolog 1Claudin-low cell linesBreast cancer stem cellsCancer stem cellsOncogene homolog 1Gli1 expressionBreast cancerClaudin-low breast cancer subtypeMetastatic breast cancer stem cellsNFκB pathwayCell linesClaudin-low breast cancerActivated B cells (NF-κB) pathwayClaudin-low subtypeHomolog 1Breast cancer subtypesMarkers of EMTB-cell pathwayNFκB subunit p65Stem cellsMesenchymal-like characteristicsPoor prognosisTreatment optionsOrthotopic xenograftsAggressive type
2013
MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL
Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF. MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Pigment Cell & Melanoma Research 2013, 26: 527-541. PMID: 23617806, PMCID: PMC3918898, DOI: 10.1111/pcmr.12110.Peer-Reviewed Original ResearchMeSH KeywordsAxl Receptor Tyrosine KinaseCdc42 GTP-Binding ProteinCell Line, TumorCell MovementCell ProliferationCell SurvivalC-Mer Tyrosine KinaseCytophotometryGene Expression ProfilingGene Expression Regulation, NeoplasticHEK293 CellsHumansMelanomaNeoplasm MetastasisOligonucleotide Array Sequence AnalysisPhosphorylationProto-Oncogene ProteinsReceptor Protein-Tyrosine KinasesSignal TransductionSkin NeoplasmsConceptsCell migrationCell behaviorMelanoma cellsAkt-dependent mannerShRNA-mediated knockdownDifferential cell behaviorDifferent transcriptional signaturesReceptor tyrosine kinase AXLMelanoma cell migrationMelanoma cell proliferationKinase domainTyrosine kinase AXLCell motilityTranscriptional signatureCell survivalColony formationCell proliferationOverexpression of AxlPossible therapeutic targetMelanoma pathogenesisNovel mutationsMerTKAxlTherapeutic targetMutations
2011
NFBD1/MDC1 Regulates Cav1 and Cav2 Independently of DNA Damage and p53
Wilson KA, Colavito SA, Schulz V, Wakefield PH, Sessa W, Tuck D, Stern DF. NFBD1/MDC1 Regulates Cav1 and Cav2 Independently of DNA Damage and p53. Molecular Cancer Research 2011, 9: 766-781. PMID: 21551225, PMCID: PMC3901581, DOI: 10.1158/1541-7786.mcr-10-0317.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsAtaxia Telangiectasia Mutated ProteinsCaveolin 1Caveolin 2Cell AdhesionCell Cycle ProteinsCell Line, TumorCells, CulturedChromatinDNA DamageDNA RepairDNA-Binding ProteinsFibroblastsGene Knockdown TechniquesHistonesHumansMiceNuclear ProteinsProtein Serine-Threonine KinasesRNA, MessengerSignal TransductionTrans-ActivatorsTranscription, GeneticTumor Suppressor Protein p53Tumor Suppressor ProteinsConceptsDNA damage checkpoint signalingNFBD1 knockdownDNA damageNFBD1/MDC1Focal adhesion signalingDNA repair factorsDNA damage responseP53-mediated transcriptionAdhesion signalingCheckpoint signalingRepair factorsResponsive transcriptionDamage responseMitogenic signalingNFBD1DNA repairNovel functionTransactivation activityGene pathwaysAtaxia telangiectasiaMicroarray analysisSimilar phenotypeERK phosphorylationGenesTranscription
2010
Interactions of ErbB4 and Kap1 Connect the Growth Factor and DNA Damage Response Pathways
Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 Connect the Growth Factor and DNA Damage Response Pathways. Molecular Cancer Research 2010, 8: 1388-1398. PMID: 20858735, PMCID: PMC3901583, DOI: 10.1158/1541-7786.mcr-10-0042.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorChlorocebus aethiopsCOS CellsDNA DamageDown-RegulationErbB ReceptorsGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansIntercellular Signaling Peptides and ProteinsProtein BindingReceptor, ErbB-4Repressor ProteinsSignal TransductionSilencer Elements, TranscriptionalSubstrate SpecificityTripartite Motif-Containing Protein 28ConceptsIntracellular domainKinase activityDNA damage response pathwayDamage response pathwayDNA damage responseErbB4 intracellular domainGrowth factor signalingHigh kinase activitySoluble intracellular domainExpression of genesReceptor tyrosine kinasesSuppression of MDM2Candidate interactorsDamage responseResponse pathwaysFactor signalingPlasma membraneMultiple isoformsErbB4 kinase activityTyrosine kinaseDNA damageRole of ErbB4Protein 1KAP1Conjoint regulation
2008
ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer
Stern DF. ERBB3/HER3 and ERBB2/HER2 Duet in Mammary Development and Breast Cancer. Journal Of Mammary Gland Biology And Neoplasia 2008, 13: 215. PMID: 18454306, PMCID: PMC6590701, DOI: 10.1007/s10911-008-9083-7.Peer-Reviewed Original ResearchConceptsBreast cancerCancer etiologyErbB3/HER3Breast cancer etiologyAdditional therapeutic opportunitiesEpidermal growth factor receptor familyGrowth factor receptor familyAkt-dependent pathwayFactor receptor familyMouse modelERBB2 amplificationNeuregulin-2Neuregulin-1Therapeutic opportunitiesTherapeutic toolMammary developmentRegulation of metabolismCancerReceptor familyAggressive propertiesTherapeutic compoundsErbB2ErbB3Eventual developmentEtiologyRegulation of the Rad53 protein kinase in signal amplification by oligomer assembly and disassembly
Jia-Lin Ma N, Stern DF. Regulation of the Rad53 protein kinase in signal amplification by oligomer assembly and disassembly. Cell Cycle 2008, 7: 808-817. PMID: 18239457, DOI: 10.4161/cc.7.6.5595.Peer-Reviewed Original ResearchConceptsRad53 activationDNA damageOligomer assemblyRad53 kinase activityRad53 protein kinaseAbsence of Mec1DNA damage responseSignal transduction processesMammalian Chk2Autophosphorylation activityGenetic requirementsCheckpoint responseChk2 activationDamage responseEffector kinaseProtein kinaseKinase activityRad53Forms oligomersTransduction processesSCD domainsInduced oligomerizationOligomer formationOligomerizationChk2
2005
Relationship of Epidermal Growth Factor Receptor Expression to ErbB-2 Signaling Activity and Prognosis in Breast Cancer Patients
DiGiovanna MP, Stern DF, Edgerton SM, Whalen SG, Moore D, Thor AD. Relationship of Epidermal Growth Factor Receptor Expression to ErbB-2 Signaling Activity and Prognosis in Breast Cancer Patients. Journal Of Clinical Oncology 2005, 23: 1152-1160. PMID: 15718311, DOI: 10.1200/jco.2005.09.055.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptor expressionGrowth factor receptor expressionBreast cancer patientsBreast cancerHuman breast cancerFactor receptor expressionErbB-2Cancer patientsReceptor expressionEGFR expressionEarly-stage breast cancerAdverse prognostic valueErbB-2 phosphorylationFirst clinical evidenceInvasive breast cancerPrognosis of patientsPercent of tumorsParaffin tumor sectionsErbB-2 activationErbB-2 overexpressionLigand-dependent mechanismTreatment of tumorsClinical evidencePrognostic valueShorter survivalThe Plk1 Polo Box Domain Mediates a Cell Cycle and DNA Damage Regulated Interaction with Chk2
Tsvetkov LM, Tsekova RT, Xu X, Stern DF. The Plk1 Polo Box Domain Mediates a Cell Cycle and DNA Damage Regulated Interaction with Chk2. Cell Cycle 2005, 4: 602-610. PMID: 15876876, DOI: 10.4161/cc.4.4.1599.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCatalytic DomainCell CycleCell Cycle ProteinsCell DivisionCell SeparationCheckpoint Kinase 2DNA DamageDNA RepairG2 PhaseGenetic VectorsGlutathione TransferaseHeLa CellsHumansImmunoblottingImmunoprecipitationIn Vitro TechniquesMitosisPhosphorylationProtein BindingProtein KinasesProtein Serine-Threonine KinasesProtein Structure, TertiaryProto-Oncogene ProteinsSignal TransductionConceptsPlk1 polo-box domainDNA damage checkpointPolo-box domainPolo-like kinase 1Eukaryotic proteinsDamage checkpointMitotic regulationBox domainRegulated interactionPlk1 activityProtein kinaseSignaling cascadesChk2Kinase 1Tumor suppressorCell cycleDNA damageS phasePlk1M phaseMitosisMultiple processesPotential mechanismsPhosphorylatesKinase