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 residuesHeparin 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
Structure, 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 ResearchMeSH KeywordsCrystallography, X-RayCytoplasmHumansImage Processing, Computer-AssistedModels, MolecularProtein MultimerizationProtein Structure, TertiaryProto-Oncogene Proteins c-kitStem Cell FactorConceptsExtracellular 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 structureAutophosphorylationDimersKinase
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