2020
Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi
Lim C, Berk JM, Blaise A, Bircher J, Koleske AJ, Hochstrasser M, Xiong Y. Crystal structure of a guanine nucleotide exchange factor encoded by the scrub typhus pathogen Orientia tsutsugamushi. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30380-30390. PMID: 33184172, PMCID: PMC7720168, DOI: 10.1073/pnas.2018163117.Peer-Reviewed Original ResearchConceptsBacterial GEFStructure-guided mutational analysisExchange factor domainRho family GTPasesObvious sequence similarityRho GTPases Rac1Pathogen Orientia tsutsugamushiAlters cell morphologyInteraction screenConvergent evolutionGEF domainHost interactorsExchange factorNucleotide displacementGEF activityCellular processesSequence similarityCytoskeletal structuresGTPases Rac1Ectopic expressionMutational analysisGEFRac1Factor domainPathogenic bacterium
2019
Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits
Katrancha SM, Shaw JE, Zhao AY, Myers SA, Cocco AR, Jeng AT, Zhu M, Pittenger C, Greer CA, Carr SA, Xiao X, Koleske AJ. Trio Haploinsufficiency Causes Neurodevelopmental Disease-Associated Deficits. Cell Reports 2019, 26: 2805-2817.e9. PMID: 30840899, PMCID: PMC6436967, DOI: 10.1016/j.celrep.2019.02.022.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGuanine Nucleotide Exchange FactorsHumansMaleMiceMice, KnockoutNeurodevelopmental DisordersNeuronsProtein Serine-Threonine KinasesSynapsesConceptsHeterozygous coding mutationsDendritic spine densityHippocampus of miceNeurodevelopmental disordersLong-term potentiationDendritic spine defectsPostsynaptic deficitsSpine densityCortical synapsesDendritic arborizationExcitatory neuronsMotor coordinationHaploinsufficient miceKnockout miceTherapeutic interventionsBipolar disorderProtein kinase A (PKA) signalingNeuronal structuresSpine defectsIncreases anxietyMiceDisordersDeficitsCoding mutationsA Signaling
2017
Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity
Katrancha SM, Wu Y, Zhu M, Eipper BA, Koleske AJ, Mains RE. Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity. Human Molecular Genetics 2017, 26: 4728-4740. PMID: 28973398, PMCID: PMC5886096, DOI: 10.1093/hmg/ddx355.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsDatabases, Nucleic AcidGuanine Nucleotide Exchange FactorsGuanosine DiphosphateGuanosine TriphosphateHEK293 CellsHumansMiceMice, KnockoutMutationNeurodevelopmental DisordersProtein DomainsProtein Serine-Threonine KinasesRac1 GTP-Binding ProteinRho GTP-Binding ProteinsRhoA GTP-Binding ProteinConceptsDe novo mutationsNeurodevelopmental disordersRare sequence variantsTriple functional domain proteinNovo mutationsComplex neurodevelopmental disorderBipolar disorderTherapeutic progressSequence variantsImpaired inhibitionProtein levelsDisordersMolecular pathwaysMillions of peopleIntellectual disabilityRare variantsNeurite outgrowthGenetic damageFactor activityMutationsExchange factor activityDistinct specificitiesPoor understandingRac1ActivityBrain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity
Miller MB, Yan Y, Machida K, Kiraly DD, Levy AD, Wu YI, Lam TT, Abbott T, Koleske AJ, Eipper BA, Mains RE. Brain Region and Isoform-Specific Phosphorylation Alters Kalirin SH2 Domain Interaction Sites and Calpain Sensitivity. ACS Chemical Neuroscience 2017, 8: 1554-1569. PMID: 28418645, PMCID: PMC5517348, DOI: 10.1021/acschemneuro.7b00076.Peer-Reviewed Original ResearchConceptsLong-term potentiationCalpain sensitivityEffects of cocaineRat nucleus accumbensAdult rat nucleus accumbensRho GDP/GTP exchange factorRegion-specific effectsChronic cocaineNucleus accumbensSynaptic functionBrain regionsKALRN geneSpine morphologyPrefrontal cortexKal7CocainePotentiationFunctional significanceCalpainPhosphorylationPhosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells
Rosenberg BJ, Gil-Henn H, Mader CC, Halo T, Yin T, Condeelis J, Machida K, Wu YI, Koleske AJ. Phosphorylated cortactin recruits Vav2 guanine nucleotide exchange factor to activate Rac3 and promote invadopodial function in invasive breast cancer cells. Molecular Biology Of The Cell 2017, 28: 1347-1360. PMID: 28356423, PMCID: PMC5426849, DOI: 10.1091/mbc.e16-12-0885.Peer-Reviewed Original ResearchConceptsInvasive breast cancer cellsInvadopodium maturationBreast cancer cellsActin nucleation-promoting factorCancer cellsSH2 domain bindsHuman SH2 domainsMatrix degradationNucleation-promoting factorsGuanine nucleotide exchange factor Vav2Actin-rich protrusionsSubsequent cell invasionExchange factor Vav2Active Rac3Invasive MDA-MB-231 breast cancer cellsMDA-MB-231 breast cancer cellsInvadopodial functionSH2 domainDomain bindsExchange factorKinase cascadeCortactin phosphorylationActin polymerizationMutant formsInvadopodia
2004
Adhesion-Dependent Regulation of p190RhoGAP in the Developing Brain by the Abl-Related Gene Tyrosine Kinase
Hernández SE, Settleman J, Koleske AJ. Adhesion-Dependent Regulation of p190RhoGAP in the Developing Brain by the Abl-Related Gene Tyrosine Kinase. Current Biology 2004, 14: 691-696. PMID: 15084284, DOI: 10.1016/j.cub.2004.03.062.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsBrainCytoskeletonDNA-Binding ProteinsGTPase-Activating ProteinsGuanine Nucleotide Exchange FactorsImmunoblottingMiceMorphogenesisNeuritesNeuronsNuclear ProteinsPhosphorylationPlasmidsPrecipitin TestsProtein-Tyrosine KinasesRepressor ProteinsTransfectionTumor Cells, CulturedConceptsAdhesion-dependent regulationArg substrateNeuronal morphogenesisKinase activityGene Tyrosine KinaseActin-dependent processesWild-type extractsWild-type cellsArg kinase activityAbl kinase activityMembrane rufflingPostnatal mouse brainFamily kinasesCytoskeletal rearrangementsPhosphotyrosine contentFilopodial protrusionsCell motilityArg kinaseP190RhoGAPMouse brainTyrosine kinaseKinasePhosphorylationMorphogenesisPostnatal brain