2021
PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK
Cho E, Lou HJ, Kuruvilla L, Calderwood DA, Turk BE. PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK. Cell Reports 2021, 34: 108928. PMID: 33789117, PMCID: PMC8068315, DOI: 10.1016/j.celrep.2021.108928.Peer-Reviewed Original ResearchConceptsProtein kinase cascadeCore oncogenic pathwaysKey negative regulatorOncogenic ERKERK pathway activationCrosstalk regulationCentral kinaseKinase cascadePhosphorylation sitesRegulatory subunitRaf-MEKNegative regulatorERK pathwayDrug targetsOncogenic pathwaysMEKMEK inhibitorsDephosphorylationPathway activationPPP6CPhosphatasePathwayERKHyperphosphorylationCascade
2020
Differences in self-association between kindlin-2 and kindlin-3 are associated with differential integrin binding
Kadry YA, Maisuria EM, Huet-Calderwood C, Calderwood DA. Differences in self-association between kindlin-2 and kindlin-3 are associated with differential integrin binding. Journal Of Biological Chemistry 2020, 295: 11161-11173. PMID: 32546480, PMCID: PMC7415974, DOI: 10.1074/jbc.ra120.013618.Peer-Reviewed Original ResearchConceptsKindlin-3Kindlin-2Focal adhesionsIntegrin cytoplasmic domainTransmembrane adhesion receptorsComparative sequence analysisLive-cell imagingAbility of cellsCytoplasmic domainF3 subdomainsMammalian cellsCytoplasmic componentsExtracellular environmentAdhesion receptorsKindlinSequence analysisIntegrin familySelf-associationIntegrin bindingPhysiological importanceMolecular levelPoint mutationsProteinCellsAdhesion
2019
The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences
Sun X, Su VL, Calderwood DA. The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences. Journal Of Biological Chemistry 2019, 294: 14319-14332. PMID: 31391252, PMCID: PMC6768646, DOI: 10.1074/jbc.ra119.007692.Peer-Reviewed Original ResearchConceptsCell-cell contactCell-cell junctionsPolybasic sequenceP21-activated kinaseSmall GTPases RacVariable regionsCell-cell boundariesPAK regulationDomain organizationCdc42 bindingAdhesion dynamicsCRIB domainGTPases RacSubcellular localizationTruncation mutantsKinase domainKinase effectorsCellular signalsExtensive similaritySequence regionsPAK1Cell adhesionCdc42PAKKinaseFilamin A mediates isotropic distribution of applied force across the actin network
Kumar A, Shutova MS, Tanaka K, Iwamoto DV, Calderwood DA, Svitkina TM, Schwartz MA. Filamin A mediates isotropic distribution of applied force across the actin network. Journal Of Cell Biology 2019, 218: 2481-2491. PMID: 31315944, PMCID: PMC6683746, DOI: 10.1083/jcb.201901086.Peer-Reviewed Original ResearchConceptsTalin tension sensorStress fibersActin networkFilamin ACortical actin networkCortical actin filamentsIntegrin-mediated adhesionActin cytoskeletonFocal adhesionsCortical actinFLNA knockdownActin filamentsTalinKnockdownCell sensingDirection of stretchTension sensorPhysiology of muscleUniaxial stretchForce transmissionCytoskeletonStrainsStretchAdhesionReexpression
2017
Novel ecto-tagged integrins reveal their trafficking in live cells
Huet-Calderwood C, Rivera-Molina F, Iwamoto DV, Kromann EB, Toomre D, Calderwood DA. Novel ecto-tagged integrins reveal their trafficking in live cells. Nature Communications 2017, 8: 570. PMID: 28924207, PMCID: PMC5603536, DOI: 10.1038/s41467-017-00646-w.Peer-Reviewed Original ResearchConceptsIntegrin functionΒ1 integrinLive cellsCell surface adhesion receptorsHeterodimeric cell-surface adhesion receptorsIntegrin endocytosisMulticellular organismsNovel powerful toolFocal adhesionsKnockout fibroblastsIntegrin activationAdhesion receptorsExtracellular loopIntegrinsTraffickingMajor mysteriesCellsTagsAdhesionHaloTagEndocytosisPowerful toolExocytosisOrganismsVesicles
2016
Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus*
Draheim KM, Huet-Calderwood C, Simon B, Calderwood DA. Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus*. Journal Of Biological Chemistry 2016, 292: 1884-1898. PMID: 28003363, PMCID: PMC5290960, DOI: 10.1074/jbc.m116.762393.Peer-Reviewed Original ResearchLoss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms
Shi X, Mihaylova VT, Kuruvilla L, Chen F, Viviano S, Baldassarre M, Sperandio D, Martinez R, Yue P, Bates JG, Breckenridge DG, Schlessinger J, Turk BE, Calderwood DA. Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: e4558-e4566. PMID: 27432991, PMCID: PMC4978292, DOI: 10.1073/pnas.1608319113.Peer-Reviewed Original ResearchMeSH KeywordsAzepinesCell Line, TumorCell ProliferationColorectal NeoplasmsDrug ResistanceGene Expression Regulation, NeoplasticHCT116 CellsHEK293 CellsHumansMolecular StructureProteinsProto-Oncogene Proteins c-mycReceptors, Transforming Growth Factor betaRNA InterferenceSignal TransductionTranscription FactorsTransforming Growth Factor betaTriazolesConceptsTGF-β receptor activityExtraterminal domain protein inhibitorsRegulation of MYCCancer cellsBET bromodomain inhibitionShRNA screeningProtein 33TGF-β receptor expressionBromodomain inhibitorsProtein inhibitorInhibition of TGFColorectal cancer cellsBromodomain inhibitionBETi resistanceCancer therapeuticsNew therapeutic benefitsDurable responsesMYCDependent mechanismReceptor expressionTherapeutic benefitBETiReceptor activityResistant stateAntiproliferative effects
2015
Direct Interactions with the Integrin β1 Cytoplasmic Tail Activate the Abl2/Arg Kinase*
Simpson MA, Bradley WD, Harburger D, Parsons M, Calderwood DA, Koleske AJ. Direct Interactions with the Integrin β1 Cytoplasmic Tail Activate the Abl2/Arg Kinase*. Journal Of Biological Chemistry 2015, 290: 8360-8372. PMID: 25694433, PMCID: PMC4375489, DOI: 10.1074/jbc.m115.638874.Peer-Reviewed Original ResearchConceptsIntegrin β1 cytoplasmic tailExtracellular matrix adhesion receptorsSrc homology domainFibroblast cell motilityIntegrin β1Β1 cytoplasmic tailMembrane-proximal segmentAdhesion complex formationMatrix adhesion receptorsNonreceptor tyrosine kinaseArg kinase activityArg nonreceptor tyrosine kinaseCancer cell invasivenessHomology domainActin cytoskeletonCytoplasmic tailCytoskeletal remodelingDendrite morphogenesisTyr-783Kinase domainPhosphorylated regionAbl familyΒ1 tailArg kinaseCell motilityPAK6 targets to cell–cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape
Morse EM, Sun X, Olberding JR, Ha BH, Boggon TJ, Calderwood DA. PAK6 targets to cell–cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape. Journal Of Cell Science 2015, 129: 380-393. PMID: 26598554, PMCID: PMC4732285, DOI: 10.1242/jcs.177493.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAntigens, CDCadherinsCdc42 GTP-Binding ProteinCell AdhesionCell Line, TumorEpithelial CellsHEK293 CellsHumansIntercellular JunctionsMolecular Sequence DataP21-Activated KinasesProtein BindingProtein Interaction Domains and MotifsProtein Sorting SignalsProtein TransportConceptsCell-cell adhesionN-terminusCdc42/Rac interactive binding (CRIB) domainSerine/threonine kinaseP21-activated kinase (PAK) familyCdc42-dependent mannerPolybasic regionThreonine kinaseCdc42 knockdownKinase familyBinding domainsKinase activityImportant regulatorCell adhesionPAK6Broader rolePAKAdhesionTargetingCdc42PAK1KinaseKnockdownRegulatorMutations
2014
Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation
Huet-Calderwood C, Brahme NN, Kumar N, Stiegler AL, Raghavan S, Boggon TJ, Calderwood DA. Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation. Journal Of Cell Science 2014, 127: 4308-4321. PMID: 25086068, PMCID: PMC4179494, DOI: 10.1242/jcs.155879.Peer-Reviewed Original ResearchConceptsIntegrin activationKindlin-2Kindlin-3Focal adhesion proteinsFunctional differencesIntegrin-linked kinaseILK complexAdhesion proteinsF2 subdomainMolecular basisIsoform specificityComplex bindsKindlinFA targetingActivation defectsCell adhesionActivationFALocalizesKinaseGFPSignalingILKIsoformsProtein
2013
Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6
Gao J, Ha BH, Lou HJ, Morse EM, Zhang R, Calderwood DA, Turk BE, Boggon TJ. Substrate and Inhibitor Specificity of the Type II p21-Activated Kinase, PAK6. PLOS ONE 2013, 8: e77818. PMID: 24204982, PMCID: PMC3810134, DOI: 10.1371/journal.pone.0077818.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceCatalytic DomainCrystallizationCrystallography, X-RayHEK293 CellsHumansIndolesModels, MolecularMolecular Sequence DataP21-Activated KinasesPeptide FragmentsPhosphorylationProtein ConformationPyrazolesPyrrolesSequence Homology, Amino AcidSignal TransductionSubstrate SpecificitySunitinibConceptsP21-activated kinaseCo-crystal structureRho family small GTPasesPeptide substrate specificityATP-competitive inhibitorsStructure-function relationshipsSmall GTPasesPAK familyCatalytic domainMelanoma-associated mutationsSubstrate specificityInhibitor specificityPAK6Receptor signalingPF-3758309Important effectors