OMIMOnlineMendelianInheritanceinManAll DatabasesPubMedNucleotideProteinGenomeStructurePMCTaxonomyOMIM SearchPubMedProteinNucleotideCoreNucleotideGSSESTStructureGenomeBooksCancerChromosomesConservedDomainsdbGaP3DDomainsGeneGenomeProjectGENSATGEOProfilesGEODataSetsHomoloGeneJournalsMeSHNCBIWebSiteNLMCatalogOMIAOMIMPMCPopSetProbeProteinClustersPubChemBioAssayPubChemCompoundPubChemSubstanceSNPTaxonomyToolKitUniGeneUniSTSLimitsPreview/IndexHistoryClipboardDetailsDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardAll1OMIMdbSNP0OMIMUniSTS0*601667LinksANGIOPOIETIN1ANGPT1AlternativetitlessymbolsANG1Genemaplocus8q22TEXTCLONINGTIE2(TEK600221)isareceptorliketyrosinekinaseexpressedalmostexclusivelyinendothelialcellsandearlyhematopoieticcellsandrequiredforthenormaldevelopmentofvascularstructuresduringembryogenesisDavisetal(1996)identifiedasecretedligandforTIE2termedangiopoietin1usinganovelexpressioncloningtechniquethatinvolvedintracellulartrappingandprotectionoftheligandinCOScellsThehumangeneencodesa498aminoacidpolypeptidewithpredictedcoiledcoilandfibrinogenlikedomainsThestructureofangiopoietin1differsfromthatofknownangiogenicfactorsorotherligandsforreceptortyrosinekinasesAlthoughangiopoietin1boundandinducedthetyrosinephosphorylationofTIE2itdidnotdirectlypromotethegrowthofculturedendothelialcellsHoweveritsexpressionandcloseproximitytodevelopingbloodvesselsimplicatedangiopoietin1inendothelialdevelopmentalprocessesSeealsoangiopoietin2(601922)GENEFUNCTIONFolkmanandD'Amore(1996)pointedoutthatvascularabnormalityinbothmiceandhumansisdefinedbyareceptorligandsystemonthevascularendothelialcellAnapparentdefectinvascularremodelingcanresultfromanactivatingmutationofthereceptor(Vikkulaetal1996)fromtheabsenceoftheligand(Surietal1996)orfromadeficiencyoftheTIE2receptoritself(Satoetal1995)HoweverwhileeachsituationrevealsageneralabnormalityinvascularremodelingtheremaybesubtlebutimportantdifferencesToexplorethepossibilitythatVEGF(192240)andangiopoietinscollaborateduringtumorangiogenesisHolashetal(1999)analyzedseveraldifferentmurineandhumantumormodelsTheapparentassociationoftumorvesselregressionapoptosisanddisruptionofendothelialcellinteractionswithsupportcellsinratC6gliomasraisedthepossibilitythatblockadeofthestabilizingactionofAng1mightbecontributingtotumorvesselregressionConsistentwiththispossibilityHolashetal(1999)notedthatangiopoietin1wasantiapoptoticforculturedendothelialcellsandexpressionofitsantagonistangiopoietin2wasinducedintheendotheliumofcooptedtumorvesselsbeforetheirregressionDiffuseangiopoietin1expressioninhumantumorsresembledthatseenintheratmodelHolashetal(1999)suggestedthatasubsetoftumorsrapidlycooptsexistinghostvesselstoformaninitiallywellvascularizedtumormassPerhapsaspartofahostdefensemechanismthereiswidespreadregressionoftheseinitiallycooptedvesselsleadingtoasecondarilyavasculartumorandamassivetumorcelllossHowevertheremainingtumorisultimatelyrescuedbyrobustangiogenesisatthetumormarginLoughnaandSato(2001)showedthatthecombinatorialfunctionofangiopoietin1andtheorphanreceptorTIE1(600222)iscriticalforthedevelopmentoftherighthandsidevenoussystembutisdispensableforthelefthandsidevenoussystemThisfindingrevealedtheexistenceofadistinctgeneticprogramfortheestablishmentoftherighthandsideandlefthandsidevascularnetworkswellbeforethenetworkasymmetrybecomesmorphologicallydiscernibleGevaetal(2002)investigatedVEGFAANGPT1andANGPT2transcriptprofilesandtheproteinproductsthattheyencodeinplacentasfromnormotensivepregnanciesthroughoutpregnancyQuantitativerealtimePCRanalysisdemonstratedthatVEGFAandANGPT1mRNAincreasedinalinearpatternby25%(notsignificant)and28%/week(P=0034)respectivelywhereasANGPT2decreasedlogarithmicallyby35%/week(P=00003)ANGPT2mRNAwas400and100foldhigherthanthatofANGPT1andVEGFArespectivelyinthefirsttrimesteranddeclinedto20foldand7foldinthethirdInsituhybridizationandimmunohistochemicalstudiesrevealedthatVEGFAwaslocalizedincytoandsyncytiotrophoblastandperivascularcellswhereasANGPT1andANGPT2wereonlyinsyncytiotrophoblastandperivascularcellsintheimmatureintermediatevilliduringthefirstandsecondtrimestersandmatureintermediateandterminalvilliduringthethirdtrimesterTheauthorsconcludedthatthesemoleculesmayplayimportantrolesinplacentalbiologyandchorionicvillusvasculardevelopmentandremodelinginanautocrine/paracrinemannerInteractionofhematopoieticstemcells(HSCs)withtheirparticularmicroenvironmentsknownasstemcellnichesiscriticalforadulthematopoiesisinbonemarrowAraietal(2004)demonstratedthatHSCsexpressingthereceptortyrosinekinaseTIE2arequiescentandantiapoptoticandcompriseasidepopulationofHSCsthatadheretoosteoblastsinthebonemarrownicheTheinteractionofTIE2withitsligandANG1inducedcobblestoneformationofHSCsinvitroandmaintainedinvivolongtermrepopulatingactivityofHSCsFurthermoreANG1enhancedtheabilityofHSCstobecomequiescentandinducedadhesiontoboneresultinginprotectionoftheHSCcompartmentfrommyelosuppressivestressThesedatasuggestedthattheTIE2/ANG1signalingpathwayplaysacriticalroleinthemaintenanceofHSCsinaquiescentstateinthebonemarrownicheGENESTRUCTUREWardetal(2001)determinedthattheANGPT1genecontains9exonsandspans483kbExons1to5encodetheNterminusthecoiledcoildomainandpartofthehingeregionandexons5to9encodetheremainderofthehingeregionthefibrinogen(see134820)likedomainandtheCterminusMAPPINGByFISHandradiationhybridanalysisCheungetal(1998)mappedtheANGPT1geneto8q223q23UsingradiationhybridanalysisandFISHGrosiosetal(1999)alsomappedtheANGPT1genetochromosome8q223q23ByFISHValenzuelaetal(1999)mappedtheANGPT1geneto8q22inaregionthatshowshomologyofsyntenytomousechromosome15wheretheymappedthemouseAngpt1geneHoweverbyindirectinsituPCRandFISHMarzilianoetal(1999)mappedtheAngpt1geneinthemousetochromosome9E2ANIMALMODELSurietal(1996)showedthatmiceengineeredtolackangiopoietin1displayangiogenicdefectsreminiscentofthosepreviouslyseeninmicelackingTie2demonstratingthatangiopoietin1isaprimaryphysiologicligandforTie2andthatithascriticalinvivoangiogenicactionsthataredistinctfromvascularendothelialgrowthfactor(VEGF192240)andthatarenotreflectedintheclassicinvitroassaysusedtocharacterizeVEGFTheyconcludedthatangiopoietin1appearstoplayacrucialroleinmediatingreciprocalinteractionsbetweentheendotheliumandsurroundingmatrixandmesenchymeTargetedgeneinactivationstudiesinmiceshowthatvascularendothelialgrowthfactorisnecessaryfortheearlystagesofvasculardevelopmentandthatangiopoietin1isrequiredforthelaterstagesofvascularremodelingSurietal(1998)showedthattransgenicoverexpressionofangiopoietin1intheskinofmiceproduceslargermorenumerousandmorehighlybranchedvesselsTheseresultsraisedthepossibilitythatangiopoietinscanbeusedaloneorincombinationwithVEGFtopromotetherapeuticangiogenesisThurstonetal(1999)comparedtransgenicmiceoverexpressingeitherVegforAng1intheskinVegfinducedbloodvesselswereleakywhereasthoseinducedbyAng1werenotMoreovervesselsinAng1overexpressingmicewereresistanttoleakscausedbyinflammatoryagentsCoexpressionofAng1andVegfhadanadditiveeffectonangiogenesisbutresultedinleakageresistantvesselstypicalofAng1Thurstonetal(1999)concludedthatANG1thereforemaybeusefulforreducingmicrovascularleakageindiseasesinwhichtheleakageresultsfromchronicinflammationorelevatedVEFGandincombinationwithVEGFforpromotinggrowthofnonleakyvesselsSEEALSOHanahan(1997)REFERENCES1AraiFHiraoAOhmuraMSatoHMatsuokaSTakuboKItoKKohGYSudaTTie2/Angiopoietin1signalingregulateshematopoieticstemcellquiescenceinthebonemarrownicheCell1181491612004PubMedID152609862CheungAHStewartRJMarsdenPAEndothelialTie2/Tekligandsangiopoietin1(ANGPT1)andangiopoietin2(ANGPT2)regionallocalizationofthehumangenesto8q223q23and8p23Genomics483893911998PubMedID95456483DavisSAldrichTHJonesPFAchesonAComptonDLJainVRyanTEBrunoJRadziejewskiCMaisonpierrePCYancopoulosGDIsolationofangiopoietin1aligandfortheTIE2receptorbysecretiontrapexpressioncloningCell87116111691996PubMedID89802234FolkmanJD'AmorePABloodvesselformationwhatisitsmolecularbasis?Cell87115311551996PubMedID89802215GevaEGinzingerDGZaloudekCJMooreDHByrneAJaffeRBHumanplacentalvasculardevelopmentvasculogenicandangiogenic(branchingandnonbranching)transformationisregulatedbyvascularendothelialgrowthfactorAangiopoietin1andangiopoietin2JClinEncodrMetab874213422420026GrosiosKLeekJPMarkhamAFYancopoulosGDJonesPFAssignmentofANGPT4ANGPT1andANGPT2encodingAngiopoietins41and2tohumanchromosomebands20p138q223q23and8p231respectivelybyinsituhybridizationandradiationhybridmappingCytogenetCellGenet841181201999PubMedID103431247HanahanDSignalingvascularmorphogenesisandmaintenanceScience27748501997PubMedID92297728HolashJMaisonpierrePCComptonDBolandPAlexanderCRZagzagDYancopoulosGDWiegandSJVesselcooptionregressionandgrowthintumorsmediatedbyangiopoietinsandVEGFScience284199419981999PubMedID103731199LoughnaSSatoTNAcombinatorialroleofangiopoietin1andorphanreceptorTIE1pathwaysinestablishingvascularpolarityduringangiogenesisMolecCell72332392001PubMedID1117272810MarzilianoNCrovellaSAuderoEPecileVBussolinoFAmorosoAGaragnaSGeneticmappingofthemousehomologueofthehumanangiopoietin1gene(Agpt)tomousechromosome9E2byinsituhybridizationCytogenetCellGenet871992001999PubMedID1070266711SatoTNTozawaYDeutschUWolburgBuchholzKFujiwaraYGendronMaguireMGridleyTWolburgHRisauWQinYDistinctrolesofthereceptortyrosinekinasesTie1andTie2inbloodvesselformationNature37670731995PubMedID759643712SuriCJonesPFPatanSBartunkovaSMaisonpierrePCDavisSSatoTNYancopoulosGDRequisiteroleofangiopoietin1aligandfortheTIE2receptorduringembryonicangiogenesisCell87117111801996PubMedID898022413SuriCMcClainJThurstonGMcDonaldDMZhouHOldmixonEHSatoTNYancopoulosGDIncreasedvascularizationinmiceoverexpressingangiopoietin1Science2824684711998PubMedID977427214ThurstonGSuriCSmithKMcClainJSatoTNYancopoulosGDMcDonaldDMLeakageresistantbloodvesselsinmicetransgenicallyoverexpressingangiopoietin1Science286251125141999PubMedID1061746715ValenzuelaDMGriffithsJARojasJAldrichTHJonesPFZhouHMcClainJCopelandNGGilbertDJJenkinsNAHuangTPapadopoulosNMaisonpierrePCDavisSYancopoulosGDAngiopoietins3and4diverginggenecounterpartsinmiceandhumansProcNatAcadSci96190419091999PubMedID1005156716VikkulaMBoonLMCarrawayKLIIICalvertJTDiamontiAJGoumnerovBPasykKAMarchukDAWarmanMLCantleyLCMullikenJBOlsenBRVasculardysmorphogenesiscausedbyanactivatingmutationinthereceptortyrosinekinaseTIE2Cell87118111901996PubMedID898022517WardEGGrosiosKMarkhamAFJonesPFGenomicstructuresofthehumanangiopoietinsshowpolymorphisminangiopoietin2CytogenetCellGenet941471542001PubMedID11856872CONTRIBUTORSPatriciaAHartzupdated8/23/2005StylianosEAntonarakisupdated8/17/2004JohnAPhillipsIIIupdated12/16/2002CarolABocchiniupdated2/15/2001StylianosEAntonarakisupdated1/31/2001AdaHamoshupdated12/27/1999AdaHamoshupdated6/17/1999VictorAMcKusickupdated3/23/1999CarolABocchiniupdated3/8/1999VictorAMcKusickupdated10/14/1998CREATIONDATEVictorAMcKusick2/6/1997EDITHISTORYmgross8/23/2005mgross8/23/2005mgross8/17/2004alopez12/16/2002alopez12/16/2002carol2/15/2001mgross1/31/2001alopez12/27/1999carol10/21/1999alopez6/17/1999alopez6/17/1999alopez6/17/1999mgross4/7/1999mgross4/5/1999terry3/23/1999carol3/11/1999terry3/9/1999carol3/8/1999terry10/14/1998mark7/9/1997terry7/9/1997mark4/9/1997terry2/7/1997terry2/6/1997terry2/6/1997mark2/6/1997Copyright©19662007JohnsHopkinsUniversityDisplayTitlesDetailedClinicalSynopsisAllelicVariantsASN1XMLLinkOutRelatedEntriesBookLinksGeneLinksGenomeLinksGEOProfileLinksHomoloGeneLinksNucleotideLinksOMIALinksPubChemBioAssayLinksPMCLinksProteinLinksPubMed(calculated)LinksPubMed(cited)LinksSNPLinksGeneGenotypeLinksStructureLinksUniGeneLinksUniSTSLinksShow5102050100200500SendtoTextFilePrinterClipboardDisclaimerWritetotheHelpDeskPrivacyPolicyNCBINLMNIH