Signaling by the B Cell Receptor (BCR) (Homo sapiens)

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ArcPathVisio Brace Ellipse EndoplasmicReticulum GolgiApparatus HexagonPathVisio MimDegradation Mitochondria Octagon PentagonPathVisio Rectangle RoundedRectangle SarcoplasmicReticulum TriangleEquilateralEast TrianglePathVisio none endoplasmic reticulum lumennucleoplasmplasma membranecytosolMALT1Ca2+ADPp-Y139-DAPP1:PLCG2:PIP3PRKCBNCK1ADPPhosphorylatedNFATC1,2,3Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1RASGRP1,3DephosphorylatedNFATC1,2,3(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)CARMA1 oligomerMAP3K7PI(4,5)P2VAV1DAPP1NAc-CD22homo-oligomerCALM1ADPCalcineurin:Phosphorylated NFATC1,2,3STIM1:TRPC1ADPCD19 SignalosomeAntigenNF-kappaBp50,p65,c-Rel:ub-p-IKBATPFKBP1A:TacrolimusBCAP SignalosomeCALM1:4xCa2+ADPp-CD19:VAV1UbATPNAc-CD22p-4Y-PIK3AP1Antigen:p-BCR:SYKTRPC1GTPAntigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:BTK:NCK1:VAV1:PLCG2BLNK:GRB2:SOS1:CIN85CD22:Antigen:p-BCRATPActivated PKC betaPTPN6:p-Y762,807,822-CD22:Antigen:p-BCRADPNF-kappa-Bp50,p65,c-Rel:IKBATPp-CARMA1:MALT1:p-BCL10:TAK1ATPNF-kappa-Bp50,p65,c-Rel:p-IKBPIK3CD:PIK3R1DAGp-RASGRP1,3:DAGPSCD22LYN,FYN,BLKp-Y762,807,822-CD22:Antigen:p-BCRATPPTPN6CD19:VAV1Ca2+PLCG2Ca2+CRAC channelCyclophilinA:Cyclosporin AITPR:I(1,4,5)P3tetramerp21 RAS:GDPPI(4,5)P2ATPNF-kappaBp50,p65,c-Rel dimerCHUK:IKBKB:IKBKGMyrG2-PalmC3-LYNp-CARMA1:MALT1:p-BCL10BCRATPATPPI(3,4,5)P3Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y551-BTK:NCK1:VAV1:PLCG2Active IKK complexPIP3 activates AKTsignalingAntigen:p-BCR:p-SYKAntigen:BCRp-CARMA1:MALT1:p-BCL10:TAK1:IKKAntigen:p-BCRCalcineurin (CaN)BTKp-BCL10ADPGDPp-CARMA1 OligomerLYN, p-SYKORAI dimerSTIM1:CalciumATPIP3 receptorhomotetramerATPATPAHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerGRB2-126S proteasomeSYKADPSTIM1 DimerATPBLNK (SLP-65)SignalosomeADPp-Y139-DAPP1:PIP3ADPADPNF-kappaBp50,p65,c-Rel dimerp21 RAS:GTPNF-kappaB:p-IkB:SCF-betaTrCPAntigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y223,Y551-BTK:NCK1:VAV1:PLCG2ADPADPI(1,4,5)P3p-S157,S161-Ub-NFKBIEp-S19,S23-Ub-NFKBIBRELARELUb-21,22-p-S32,S36-NFKBIANFKB1(1-433)p-T184-RASGRP1DAGp-T133-RASGRP3PPIACyclosporin AIGLV(23-?)Ig heavy chain V-III region CAMIg heavy chain V-II region ARH-77Ig kappa chain V-I region DaudiIGKCIg kappa chain V-III region POMIGLC7Ig lambda chain V-I region NEWMIGKV4-1(21-?)IGKV2-28Ig kappa chain V-I region GalIGKV1-5(23-?)Ig kappa chain V-I region BANIgH heavy chain V-III region VH26 precursorIg lambda chain V-I region HAAntigenIg heavy chain V-III region BROIGKV3D-20Ig lambda chain V-I region VORIg heavy chain V-III region BUTIGHMIGHV7-81(1-?)Ig kappa chain V-III region VGIg lambda chain V-III region SHIGKV2D-30Ig heavy chain V-I region HG3IGKVA18(21-?)IGHV1-2Ig heavy chain V-I region EUIg kappa chain V-II region RPMI 6410Ig lambda chain V-IV region HilIGLC3Ig lambda chain V-VI region ARIg kappa chain V region EV15Ig heavy chain V-II region MCEIg heavy chain V-II region WAHIg lambda chain V-II region MGCIg lambda chain V-III region LOIIg kappa chain V-I region HK101IGHV(1-?)Ig kappa chain V-I region DEEIg lambda chain V-IV region KernIGKV1-12Ig heavy chain V-II region NEWMIg lambda chain V-II region BOHIGHDIg lambda chain V-II region TOGIg kappa chain V-II region CumIGLC1Ig heavy chain V-III region TROIg heavy chain V-III region JONIg lambda chain V-I region NEWIg kappa chain V-I region AGIg lambda chain V region 4AIg kappa chain V-III region B6p-Y188,Y199-CD79AIg heavy chain V-II region OUp-Y762,807,822-CD22Ig lambda chain V-IV region BauIg kappa chain V-I region WesIg kappa chain V-II region FRIg heavy chain V-III region KOLp-Y196,Y207-CD79BIGLC6Ig heavy chain V-III region DOBIg lambda chain V-II region NEIIg heavy chain V-III region WEAIGLC2Ig kappa chain V-I region AUITPR3ITPR1I(1,4,5)P3ITPR2GDPS-Farn-Me-PalmS KRAS4AS-Farn-Me KRAS4BS-Farn-Me PalmS NRASS-Farn-Me-2xPalmS HRASCHUKp-S177,S181-IKBKBIKBKGp-S559,S644,S652-CARD11MAP3K7MALT1p-BCL10PPP3CBPPP3CAZn2+Fe3+PPP3R1CD79BIGLC7Ig kappa chain V-I region GalIg heavy chain V-III region CAMIGKV2-28AntigenIg lambda chain V-II region MGCIg kappa chain V-III region POMIg lambda chain V-IV region HilIg heavy chain V-II region NEWMIg lambda chain V-III region LOIIGLC3Ig lambda chain V-IV region KernIg lambda chain V-II region BOHIg lambda chain V-VI region ARIGKV3D-20Ig heavy chain V-I region EUIGKCIg kappa chain V-II region CumIg heavy chain V-III region BROIg heavy chain V-III region WEAIg kappa chain V-I region BANIg kappa chain V-I region WesIGKV4-1(21-?)IGHV1-2Ig lambda chain V-I region HAIg kappa chain V-I region AUIGHDIg heavy chain V-II region ARH-77IGLV(23-?)Ig kappa chain V-I region DEEIg lambda chain V-II region NEIIg kappa chain V-III region VGIg kappa chain V-II region RPMI 6410IGKVA18(21-?)IGHMIg lambda chain V-I region NEWIg heavy chain V-III region DOBIg lambda chain V region 4AIGLC1IGKV1-12Ig lambda chain V-III region SHIg lambda chain V-IV region BauIg heavy chain V-I region HG3IGLC6IgH heavy chain V-III region VH26 precursorIg heavy chain V-III region JONIg kappa chain V-I region DaudiIGKV2D-30Ig kappa chain V region EV15CD79AIGHV7-81(1-?)Ig heavy chain V-II region WAHIGKV1-5(23-?)Ig lambda chain V-I region NEWMIGHV(1-?)IGLC2Ig kappa chain V-II region FRIg heavy chain V-III region KOLIg kappa chain V-I region HK101Ig heavy chain V-III region BUTIg kappa chain V-I region AGIg heavy chain V-II region OUIg kappa chain V-III region B6Ig heavy chain V-II region MCEIg heavy chain V-III region TROIg lambda chain V-II region TOGIg lambda chain V-I region VORIg lambda chain V-II region NEIIGHV7-81(1-?)p-Y223,Y551-BTKIg heavy chain V-II region NEWMIGKV1-12Ig heavy chain V-II region MCEIg kappa chain V-I region GalIg lambda chain V-IV region BauIGLC6Ig kappa chain V-I region HK101Ig lambda chain V-III region SHIg heavy chain V-II region OUIGLC3SH3KBP1IGLV(23-?)NCK1IGKV3D-20Ig heavy chain V-I region EUIgH heavy chain V-III region VH26 precursorp-Y188,Y199-CD79AIGHDIGKV1-5(23-?)p-6Y-SYKIGKCIg heavy chain V-I region HG3Ig kappa chain V-I region DEEIg heavy chain V-III region CAMp-Y196,Y207-CD79BIg heavy chain V-III region TROp-Y753,Y759,Y1217-PLCG2IGKV4-1(21-?)Ig kappa chain V-III region B6IGHV1-2Ig lambda chain V-I region HASOS1GRB2-1Ig kappa chain V-I region BANIg heavy chain V-III region DOBIg heavy chain V-III region KOLIg kappa chain V-I region WesIg kappa chain V-II region FRIg heavy chain V-III region WEAIg lambda chain V-I region NEWMIGHV(1-?)Ig heavy chain V-II region ARH-77Ig lambda chain V-III region LOIIGLC7PI(3,4,5)P3Ig lambda chain V-IV region HilIg heavy chain V-III region JONIg kappa chain V-III region POMIg kappa chain V-I region DaudiIg kappa chain V-II region RPMI 6410VAV1Ig lambda chain V-IV region KernIg lambda chain V-II region BOHIGHMIGKV2-28Ig lambda chain V-II region MGCIg lambda chain V-VI region ARIg heavy chain V-III region BROIg heavy chain V-III region BUTIg kappa chain V-III region VGIg kappa chain V-I region AGIg kappa chain V-II region CumIGLC1Ig kappa chain V-I region AUIGKV2D-30IGKVA18(21-?)AntigenIGLC2Ig kappa chain V region EV15Ig lambda chain V region 4AIg heavy chain V-II region WAHIg lambda chain V-II region TOGIg lambda chain V-I region VORIg lambda chain V-I region NEWp-5Y-BLNKRELANFKBIANFKBIBNFKB1(1-433)NFKBIERELIGHDIg lambda chain V-II region TOGIg heavy chain V-III region TROIGLC1AntigenIGLC6Ig heavy chain V-III region KOLIg heavy chain V-III region DOBIg lambda chain V-II region MGCIg lambda chain V-IV region BauIGHV1-2Ig lambda chain V-IV region HilIg heavy chain V-II region OUIg lambda chain V-II region NEIIgH heavy chain V-III region VH26 precursorIg kappa chain V-I region GalIg lambda chain V region 4AIg kappa chain V-I region BANIg heavy chain V-III region BROIg kappa chain V-I region WesIg heavy chain V-III region CAMIg kappa chain V-III region B6Ig kappa chain V-I region DEEIGKV3D-20IGHV7-81(1-?)Ig lambda chain V-III region LOIIGKV4-1(21-?)Ig lambda chain V-III region SHIGLC3Ig kappa chain V-II region FRIg lambda chain V-I region NEWMIg lambda chain V-I region VORIGHV(1-?)Ig kappa chain V-I region HK101Ig lambda chain V-II region BOHIg heavy chain V-II region ARH-77IGKV2-28IGLC2Ig heavy chain V-I region HG3Ig heavy chain V-III region WEAIGLV(23-?)Ig kappa chain V-II region RPMI 6410IGLC7Ig kappa chain V-II region CumIg heavy chain V-II region NEWMp-Y196,Y207-CD79BIGKV1-5(23-?)CD22Ig kappa chain V region EV15IGKV2D-30Ig heavy chain V-II region MCEp-Y188,Y199-CD79AIg kappa chain V-I region AUIg heavy chain V-III region JONIGKVA18(21-?)Ig lambda chain V-VI region ARIGHMIGKCIg heavy chain V-II region WAHIg lambda chain V-I region NEWIg heavy chain V-III region BUTIg heavy chain V-I region EUIGKV1-12Ig lambda chain V-I region HAIg kappa chain V-I region DaudiIg kappa chain V-III region VGIg lambda chain V-IV region KernIg kappa chain V-III region POMIg kappa chain V-I region AGMALT1IKBKGCHUKp-BCL10p-S559,S644,S652-CARD11MAP3K7IKBKBUBA52(1-76)UBB(77-152)UBC(229-304)UBC(153-228)UBC(533-608)UBC(1-76)UBC(457-532)RPS27A(1-76)UBC(381-456)UBB(1-76)UBC(77-152)UBC(609-684)UBC(305-380)UBB(153-228)PIK3R1PIK3CDVAV1CD19ORAI2ORAI1IGLC7IGKV1-5(23-?)Ig lambda chain V-IV region KernIgH heavy chain V-III region VH26 precursorp-Y196,Y207-CD79BIg lambda chain V-IV region HilIg heavy chain V-III region CAMIg lambda chain V-II region TOGIg heavy chain V-III region TROIGHDIg kappa chain V-II region FRIGKVA18(21-?)Ig heavy chain V-III region DOBIg lambda chain V-II region MGCIg lambda chain V-II region NEIIg kappa chain V region EV15IGKV4-1(21-?)Ig heavy chain V-II region ARH-77Ig heavy chain V-I region HG3Ig lambda chain V-III region LOIIGLC3Ig lambda chain V-I region HAIg kappa chain V-II region Cump-Y188,Y199-CD79AAntigenIg lambda chain V-II region BOHIg kappa chain V-I region BANIGHV7-81(1-?)IGLV(23-?)Ig kappa chain V-I region HK101IGKV2-28Ig lambda chain V region 4AIg kappa chain V-I region DaudiIGLC2Ig kappa chain V-I region AGIg lambda chain V-I region NEWIg heavy chain V-III region WEAIg heavy chain V-II region MCEIGKCIGKV2D-30Ig kappa chain V-I region AUIg kappa chain V-I region WesIg lambda chain V-IV region BauIg lambda chain V-VI region ARIg lambda chain V-I region NEWMIg heavy chain V-III region BROIGLC1IGKV1-12Ig heavy chain V-II region OUIg heavy chain V-III region BUTIg kappa chain V-II region RPMI 6410p-Y762,807,822-CD22Ig heavy chain V-II region NEWMIGHMIg kappa chain V-III region POMIGHV(1-?)PTPN6Ig heavy chain V-III region KOLIGHV1-2Ig heavy chain V-I region EUIg heavy chain V-III region JONIg kappa chain V-I region DEEIg kappa chain V-III region VGIg kappa chain V-I region GalIg heavy chain V-II region WAHIg lambda chain V-III region SHIg kappa chain V-III region B6IGKV3D-20Ig lambda chain V-I region VORIGLC6SKP1BTRCFBXW11CUL1Ig heavy chain V-II region MCEIg heavy chain V-III region JONIg kappa chain V-II region CumIg lambda chain V-IV region BauIg lambda chain V-II region NEIIGLC7p-Y188,Y199-CD79AIgH heavy chain V-III region VH26 precursorIg heavy chain V-I region HG3p-6Y-SYKMyrG2-PalmC3-LYNIg kappa chain V-II region FRIGHDp-Y196,Y207-CD79BVAV1SH3KBP1IGLV(23-?)IGKV1-5(23-?)IGHV(1-?)IGHV7-81(1-?)Ig lambda chain V-IV region HilIg heavy chain V-II region WAHIg kappa chain V-I region WesIg lambda chain V-II region MGCIg kappa chain V-I region HK101Ig lambda chain V-IV region KernIg lambda chain V-III region LOIIGKCIg kappa chain V-III region POMIGKV1-12IGKV4-1(21-?)PLCG2IGKV2-28Ig heavy chain V-III region CAMIg kappa chain V-I region GalIg kappa chain V region EV15IGLC3Ig heavy chain V-III region WEAIg lambda chain V-I region HAIg lambda chain V-II region BOHIg heavy chain V-III region DOBIg kappa chain V-I region AGIg lambda chain V-II region TOGIg kappa chain V-I region DEEIg kappa chain V-II region RPMI 6410IGKVA18(21-?)Ig kappa chain V-I region DaudiIg lambda chain V region 4AIg heavy chain V-III region BROIGLC6IGLC2Ig heavy chain V-II region NEWMIg lambda chain V-I region NEWMIg heavy chain V-II region ARH-77p-5Y-BLNKPI(3,4,5)P3Ig heavy chain V-I region EUIGHV1-2Ig lambda chain V-I region NEWIg kappa chain V-I region BANIg lambda chain V-VI region ARSOS1Ig kappa chain V-III region VGAntigenIg lambda chain V-I region VORBTKGRB2-1Ig heavy chain V-III region TROIGKV3D-20Ig lambda chain V-III region SHIGKV2D-30IGHMIg kappa chain V-III region B6NCK1Ig kappa chain V-I region AUIg heavy chain V-III region BUTIg heavy chain V-II region OUIg heavy chain V-III region KOLIGLC1ORAI2ORAI1STIM1IGKV1-12Ig kappa chain V-III region B6IGLV(23-?)IGKV2D-30Ig kappa chain V-III region POMIGKVA18(21-?)Ig heavy chain V-II region WAHIg heavy chain V-II region MCEIg heavy chain V-II region NEWMIGLC2Ig kappa chain V-I region WesIg lambda chain V-II region NEIIg kappa chain V-I region GalIg lambda chain V-I region NEWAntigenIGKV2-28Ig lambda chain V-I region HAIg heavy chain V-II region OUIGKV3D-20IGKV1-5(23-?)Ig kappa chain V-I region Daudip-5Y-BLNKIGLC1Ig kappa chain V-I region AGIg kappa chain V-I region DEEIg lambda chain V-IV region KernIGHV7-81(1-?)IGHV1-2Ig kappa chain V-I region BANSH3KBP1Ig heavy chain V-I region EUIGHDIg heavy chain V-II region ARH-77IGKV4-1(21-?)Ig heavy chain V-I region HG3Ig lambda chain V-VI region ARIg heavy chain V-III region KOLIg heavy chain V-III region DOBIg kappa chain V-I region AUGRB2-1IGLC7Ig heavy chain V-III region JONIGLC6Ig lambda chain V-III region SHIg kappa chain V-II region RPMI 6410Ig heavy chain V-III region TROIg lambda chain V-II region TOGIg lambda chain V region 4AIg heavy chain V-III region WEAp-Y196,Y207-CD79BIGHMIg kappa chain V-I region HK101p-6Y-SYKIg lambda chain V-I region VORIg lambda chain V-II region BOHIGLC3Ig kappa chain V region EV15Ig lambda chain V-IV region HilIGKCIg lambda chain V-IV region BauIg lambda chain V-I region NEWMIg kappa chain V-II region CumIGHV(1-?)Ig kappa chain V-III region VGp-Y188,Y199-CD79AIgH heavy chain V-III region VH26 precursorIg kappa chain V-II region FRIg heavy chain V-III region BUTIg lambda chain V-II region MGCIg heavy chain V-III region BROIg heavy chain V-III region CAMSOS1Ig lambda chain V-III region LOIp-S559,S644,S652-CARD11ITPR1I(1,4,5)P3ITPR3ITPR2NAD+AHCYL1Ig kappa chain V-I region BANIg heavy chain V-III region WEAAntigenIg kappa chain V-I region DaudiIg kappa chain V-I region GalIGKV1-5(23-?)Ig heavy chain V-III region KOLIg lambda chain V-II region BOHIGLC7IGKV4-1(21-?)IGKVA18(21-?)Ig heavy chain V-II region OUIGKV2D-30IGLC6Ig lambda chain V-III region SHIGHDIg lambda chain V-I region HAIg heavy chain V-II region MCEIg lambda chain V-IV region KernIg lambda chain V-VI region ARIg heavy chain V-III region DOBIg kappa chain V-III region B6Ig lambda chain V-I region VORIg kappa chain V-I region DEEIg kappa chain V-III region VGIGKCIg lambda chain V-III region LOIIg heavy chain V-I region HG3Ig kappa chain V-I region WesIGKV2-28IGHV1-2Ig kappa chain V region EV15Ig heavy chain V-III region CAMIGLC2IGKV1-12Ig heavy chain V-II region NEWMIg lambda chain V-IV region HilIGLC1Ig lambda chain V-IV region BauIg kappa chain V-III region POMIg lambda chain V-I region NEWMIg kappa chain V-II region CumIGHV(1-?)Ig lambda chain V-II region NEIIg heavy chain V-III region JONIg lambda chain V-I region NEWIg kappa chain V-I region HK101Ig heavy chain V-I region EUp-Y196,Y207-CD79BIg heavy chain V-II region ARH-77IGHV7-81(1-?)Ig kappa chain V-I region AGIg kappa chain V-I region AUIGHMIg heavy chain V-II region WAHIgH heavy chain V-III region VH26 precursorp-Y188,Y199-CD79AIGLC3Ig lambda chain V-II region MGCIg lambda chain V region 4AIg kappa chain V-II region RPMI 6410Ig lambda chain V-II region TOGIg heavy chain V-III region BUTIg kappa chain V-II region FRIGLV(23-?)Ig heavy chain V-III region BROIGKV3D-20Ig heavy chain V-III region TROMyrG2-PalmC3-LYNMyrG2-PalmC3,6-FYNMyrG2-BLKSOS1GRB2-1SH3KBP1BLNKPPP3CBCa2+p-12S-NFATC1PPP3CAp-14S-NFATC2p-13S-NFATC3CALM1Fe3+Zn2+PPP3R1Ig lambda chain V-II region BOHIg kappa chain V-III region POMIGHDIg lambda chain V-I region HAIg kappa chain V-I region DaudiIGLC6Ig kappa chain V-I region GalIg lambda chain V-II region TOGIg lambda chain V-IV region BauIg heavy chain V-III region BUTIg heavy chain V-III region JONp-5Y-BLNKIg heavy chain V-II region OUIg kappa chain V-I region AGIg lambda chain V-III region SHp-6Y-SYKIGLC7Ig heavy chain V-III region BROIg heavy chain V-III region WEAIg kappa chain V-II region FRIg lambda chain V-III region LOIIg lambda chain V-IV region KernPI(3,4,5)P3Ig lambda chain V-I region NEWIg heavy chain V-III region CAMIGLC1IGLV(23-?)Ig lambda chain V region 4AIg kappa chain V-I region WesIGKV4-1(21-?)IGLC2Ig lambda chain V-II region NEIIg heavy chain V-II region ARH-77Ig heavy chain V-II region MCEIg kappa chain V-III region B6Ig heavy chain V-II region WAHIGHV7-81(1-?)Ig lambda chain V-II region MGCGRB2-1VAV1IGKV1-5(23-?)IGKV1-12IGHMSOS1IGKV2D-30IGHV(1-?)p-Y196,Y207-CD79BIg heavy chain V-III region KOLIg kappa chain V-II region CumIGKCIg kappa chain V-I region HK101Ig heavy chain V-III region TROIg kappa chain V-I region AUIg lambda chain V-VI region ARIg heavy chain V-I region EUIg kappa chain V-III region VGIGKVA18(21-?)Ig kappa chain V-I region BANIg heavy chain V-II region NEWMIgH heavy chain V-III region VH26 precursorIg heavy chain V-I region HG3IGHV1-2PLCG2IGKV2-28Ig kappa chain V-I region DEEAntigenSH3KBP1IGLC3p-Y223,Y551-BTKIg lambda chain V-I region VORNCK1Ig kappa chain V region EV15p-Y188,Y199-CD79AIg lambda chain V-IV region HilIg kappa chain V-II region RPMI 6410Ig lambda chain V-I region NEWMIGKV3D-20Ig heavy chain V-III region DOBPIK3R1p-4Y-PIK3AP1PIK3CDp-S257-NFATC1p-S265-NFATC3p-S243-NFATC2FKBP1ATacrolimusp-S559,S644,S652-CARD11MALT1p-BCL10Ig heavy chain V-II region OUIg heavy chain V-III region CAMIg kappa chain V-I region HK101Ig heavy chain V-III region BROIg kappa chain V-II region FRIg kappa chain V-III region POMIg lambda chain V-II region NEIIGKV3D-20IGKVA18(21-?)IGLC7Ig heavy chain V-II region MCEIg kappa chain V-I region WesIGLV(23-?)Ig kappa chain V-I region DEEIg heavy chain V-II region NEWMIg lambda chain V-I region HAIg lambda chain V-III region LOIIGHV1-2IGLC1IGKV1-5(23-?)p-Y188,Y199-CD79AIg heavy chain V-III region TROIGKCIg lambda chain V-II region MGCIGKV1-12Ig heavy chain V-III region WEAIg heavy chain V-II region WAHIg heavy chain V-III region KOLIg heavy chain V-I region EUIg lambda chain V-II region BOHIGKV2D-30Ig lambda chain V region 4AIg heavy chain V-II region ARH-77AntigenIg lambda chain V-IV region Hilp-Y196,Y207-CD79BIg lambda chain V-IV region BauIg heavy chain V-I region HG3Ig kappa chain V-I region DaudiIg kappa chain V region EV15Ig lambda chain V-III region SHIg kappa chain V-I region AGIg kappa chain V-III region B6IGHMIg lambda chain V-VI region ARIGLC3Ig heavy chain V-III region JONIg kappa chain V-I region AUIg lambda chain V-I region NEWIg kappa chain V-II region RPMI 6410IGKV2-28Ig kappa chain V-II region CumIg lambda chain V-IV region KernIGKV4-1(21-?)IGLC6Ig heavy chain V-III region BUTIg lambda chain V-II region TOGIg heavy chain V-III region DOBIg kappa chain V-III region VGIg kappa chain V-I region GalIg lambda chain V-I region NEWMIGLC2IgH heavy chain V-III region VH26 precursorIGHDSYKIg lambda chain V-I region VORIGHV(1-?)IGHV7-81(1-?)Ig kappa chain V-I region BANp-S157,S161-NFKBIERELp-S32,S36-NFKBIABTRCCUL1FBXW11p-S19,S23-NFKBIBSKP1RELANFKB1(1-433)RELARELNFKB1(1-433)Ig kappa chain V-I region AUIg heavy chain V-II region ARH-77IGLC3Ig lambda chain V region 4AIg heavy chain V-II region OUIGKVA18(21-?)Ig kappa chain V-I region HK101Ig lambda chain V-I region NEWIGLC7IgH heavy chain V-III region VH26 precursorIg kappa chain V-I region GalIg kappa chain V-II region RPMI 6410Ig kappa chain V-II region FRIGLV(23-?)IGLC6Ig lambda chain V-VI region ARp-Y196,Y207-CD79BIg kappa chain V-II region CumIg heavy chain V-III region BROIg kappa chain V-I region BANIGHMp-6Y-SYKIg lambda chain V-IV region BauIGKV1-5(23-?)Ig lambda chain V-III region LOIIGHDIg kappa chain V region EV15IGHV7-81(1-?)Ig heavy chain V-III region WEAIg lambda chain V-II region NEIIg lambda chain V-II region TOGIg heavy chain V-II region NEWMIg kappa chain V-I region DaudiIGKV2-28IGLC1IGHV1-2Ig lambda chain V-IV region HilIGKV1-12Ig kappa chain V-III region POMIg lambda chain V-IV region KernIg heavy chain V-III region DOBIGKV2D-30Ig lambda chain V-I region HAAntigenIg lambda chain V-III region SHIg heavy chain V-III region JONIg heavy chain V-III region CAMIGKV4-1(21-?)Ig heavy chain V-I region EUp-Y188,Y199-CD79AIg heavy chain V-II region MCEIg heavy chain V-III region BUTIg heavy chain V-I region HG3IGLC2Ig lambda chain V-II region MGCIg lambda chain V-II region BOHIGHV(1-?)Ig kappa chain V-III region B6Ig heavy chain V-II region WAHIg lambda chain V-I region VORIg kappa chain V-I region DEEIg lambda chain V-I region NEWMIg heavy chain V-III region KOLIg kappa chain V-III region VGIGKV3D-20Ig kappa chain V-I region AGIg kappa chain V-I region WesIg heavy chain V-III region TROIGKCITPR3ITPR2ITPR1CARD11p-Y139-DAPP1PI(3,4,5)P3Ig heavy chain V-II region OUIg kappa chain V-I region AGIGKV3D-20Ig heavy chain V-III region CAMIg lambda chain V-I region NEWIGHMIg lambda chain V-I region NEWMIg heavy chain V-II region ARH-77Ig heavy chain V-I region EUCD79BIg kappa chain V-II region RPMI 6410Ig kappa chain V-II region FRIg lambda chain V-III region SHIGKV2D-30Ig heavy chain V-III region WEAIg kappa chain V-III region B6IGHDIg lambda chain V-IV region BauIg lambda chain V-IV region KernIg heavy chain V-III region JONIGHV7-81(1-?)IGHV(1-?)IGKVA18(21-?)Ig kappa chain V-I region AUIGKCIGLC2Ig heavy chain V-III region DOBIGLV(23-?)IGLC3IgH heavy chain V-III region VH26 precursorIGLC6Ig kappa chain V-II region CumIg lambda chain V-I region HAIg lambda chain V-III region LOIIg heavy chain V-III region TROIg heavy chain V-II region MCEIg kappa chain V-I region GalIg lambda chain V-IV region HilIGLC7Ig kappa chain V-I region DEEIg kappa chain V-I region DaudiIGKV1-12Ig heavy chain V-III region BROIg lambda chain V-II region NEIIg lambda chain V-II region BOHIg lambda chain V-VI region ARIg kappa chain V-I region WesIg kappa chain V-I region HK101IGKV1-5(23-?)CD79AIGKV4-1(21-?)Ig heavy chain V-III region KOLIg heavy chain V-I region HG3Ig kappa chain V-III region POMIg heavy chain V-II region NEWMIg kappa chain V-I region BANIg lambda chain V-II region MGCIGHV1-2Ig kappa chain V-III region VGIg heavy chain V-III region BUTIg lambda chain V-I region VORIGKV2-28Ig lambda chain V region 4AIg lambda chain V-II region TOGIg heavy chain V-II region WAHIg kappa chain V region EV15IGLC1IKBKBIKBKGCHUKPSMB10PSMA8PSMD8PSMA2PSMB1PSMB2PSMC2PSMA3PSMB3PSMC5PSMD10PSMB6PSMD6PSMC3PSMA1PSMA5PSMA4PSMC1PSME4PSMD11PSMD14PSMD4PSMB8SHFM1PSMB9PSMD13PSMB11PSME3PSMD7PSMD5PSMB4PSMA7PSMD9PSMD12PSMB7PSME1PSMB5PSMD2PSME2PSMD3PSMD1PSMC6PSMA6PSMC4PSMF1GRB2-1p-6Y-CD19PIK3R1PIK3CDVAV1RASGRP1RASGRP3PI(3,4,5)P3PLCG2p-Y139-DAPP1NFKB1(1-433)p-S19,S23-NFKBIBRELARELp-S157,S161-NFKBIEp-S32,S36-NFKBIATRPC1STIM1Ca2+CALM1p-13S-NFATC3p-12S-NFATC1p-14S-NFATC2Ig heavy chain V-II region MCEIg heavy chain V-III region WEAIGLC1Ig lambda chain V-I region NEWMp-5Y-BLNKIGHDIg kappa chain V-II region RPMI 6410PLCG2Ig kappa chain V-I region AUNCK1Ig heavy chain V-II region NEWMIg lambda chain V-VI region ARBTKIg heavy chain V-III region KOLp-6Y-SYKIg heavy chain V-I region HG3IGLC2IGLC6Ig heavy chain V-I region EUIg kappa chain V-I region DEEIg lambda chain V-II region BOHIGHV7-81(1-?)Ig kappa chain V region EV15Ig kappa chain V-I region GalIGLV(23-?)IgH heavy chain V-III region VH26 precursorIg heavy chain V-II region OUIg lambda chain V-II region TOGIg kappa chain V-I region DaudiIGLC7Ig lambda chain V-IV region HilIg kappa chain V-I region WesIg kappa chain V-III region POMIg lambda chain V-I region NEWIg kappa chain V-I region HK101Ig heavy chain V-III region BUTIg heavy chain V-III region TROVAV1Ig heavy chain V-III region DOBIGKV2D-30IGKV3D-20Ig lambda chain V-IV region BauIGKVA18(21-?)PI(3,4,5)P3IGHV(1-?)Ig heavy chain V-III region BROIg heavy chain V-II region WAHIg kappa chain V-III region B6Ig lambda chain V-II region MGCIGKV1-12AntigenIg heavy chain V-III region CAMIGHV1-2SH3KBP1Ig lambda chain V-I region VORIg kappa chain V-II region Cump-Y188,Y199-CD79AIg lambda chain V-I region HAIGKV4-1(21-?)SOS1GRB2-1Ig lambda chain V-II region NEIIg lambda chain V region 4AIGHMIg heavy chain V-III region JONIg lambda chain V-III region SHIGKCIg kappa chain V-III region VGIg kappa chain V-I region BANIGLC3p-Y196,Y207-CD79BIg kappa chain V-II region FRIg lambda chain V-III region LOIIGKV1-5(23-?)Ig lambda chain V-IV region KernIg heavy chain V-II region ARH-77IGKV2-28Ig kappa chain V-I region AGVAV1p-6Y-CD19STIM1AntigenIg kappa chain V-I region GalIg kappa chain V-I region DaudiNCK1Ig kappa chain V-III region POMIg lambda chain V-II region BOHIGHV1-2IGHV(1-?)IGKV1-5(23-?)Ig kappa chain V-III region VGIGKV2-28PLCG2Ig kappa chain V region EV15Ig kappa chain V-II region FRPI(3,4,5)P3IGHMIGKCIg heavy chain V-III region BUTIGLC1Ig kappa chain V-I region BANSH3KBP1Ig heavy chain V-I region EUp-Y551-BTKIg heavy chain V-III region WEAIg heavy chain V-II region MCEIgH heavy chain V-III region VH26 precursorIg lambda chain V-I region HAIg heavy chain V-I region HG3p-Y188,Y199-CD79AIg lambda chain V-III region LOIp-5Y-BLNKIg kappa chain V-I region AGIg kappa chain V-II region RPMI 6410Ig heavy chain V-III region JONIGKV2D-30IGKV4-1(21-?)Ig kappa chain V-I region AUIGLV(23-?)Ig lambda chain V-IV region BauIg kappa chain V-III region B6Ig lambda chain V-I region NEWMIGKVA18(21-?)Ig heavy chain V-II region NEWMp-6Y-SYKIg lambda chain V-VI region ARIg kappa chain V-I region DEEIg lambda chain V-I region NEWIg kappa chain V-I region WesIg heavy chain V-III region DOBIg heavy chain V-III region TROIGLC2Ig lambda chain V-II region MGCIg lambda chain V-II region TOGVAV1IGLC3IGLC7Ig kappa chain V-II region CumIg heavy chain V-III region CAMGRB2-1IGLC6IGHDIGKV1-12Ig heavy chain V-III region BROIg heavy chain V-II region ARH-77Ig heavy chain V-II region WAHIg lambda chain V-IV region HilIg lambda chain V-I region VORIg heavy chain V-II region OUIg kappa chain V-I region HK101Ig heavy chain V-III region KOLIg lambda chain V region 4AIg lambda chain V-III region SHSOS1p-Y196,Y207-CD79BIGHV7-81(1-?)IGKV3D-20Ig lambda chain V-IV region KernIg lambda chain V-II region NEISTIM1Ca2+RELNFKB1(1-433)RELACa2+DAGPSPRKCBS-Farn-Me KRAS4BS-Farn-Me PalmS NRASGTPS-Farn-Me-2xPalmS HRASS-Farn-Me-PalmS KRAS4AName: Signaling by the B Cell Receptor (BCR)Organism: Homo sapiens


Description

Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010).
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 983705
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  70. Fagerlund R, Melén K, Cao X, Julkunen I.; ''NF-kappaB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules.''; PubMed Europe PMC Scholia
  71. Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M.; ''Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3.''; PubMed Europe PMC Scholia
  72. Dinh M, Grunberger D, Ho H, Tsing SY, Shaw D, Lee S, Barnett J, Hill RJ, Swinney DC, Bradshaw JM.; ''Activation mechanism and steady state kinetics of Bruton's tyrosine kinase.''; PubMed Europe PMC Scholia
  73. Alicia S, Angélica Z, Carlos S, Alfonso S, Vaca L.; ''STIM1 converts TRPC1 from a receptor-operated to a store-operated channel: moving TRPC1 in and out of lipid rafts.''; PubMed Europe PMC Scholia
  74. Hata D, Nakamura T, Kawakami T, Kawakami Y, Herren B, Mayumi M.; ''Tyrosine phosphorylation of MB-1, B29, and HS1 proteins in human B cells following receptor crosslinking.''; PubMed Europe PMC Scholia
  75. Wesselborg S, Fruman DA, Sagoo JK, Bierer BE, Burakoff SJ.; ''Identification of a physical interaction between calcineurin and nuclear factor of activated T cells (NFATp).''; PubMed Europe PMC Scholia
  76. Matsuda M, Paterson HF, Rodriguez R, Fensome AC, Ellis MV, Swann K, Katan M.; ''Real time fluorescence imaging of PLC gamma translocation and its interaction with the epidermal growth factor receptor.''; PubMed Europe PMC Scholia
  77. Beals CR, Clipstone NA, Ho SN, Crabtree GR.; ''Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction.''; PubMed Europe PMC Scholia
  78. Buhl AM, Pleiman CM, Rickert RC, Cambier JC.; ''Qualitative regulation of B cell antigen receptor signaling by CD19: selective requirement for PI3-kinase activation, inositol-1,4,5-trisphosphate production and Ca2+ mobilization.''; PubMed Europe PMC Scholia
  79. Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS.; ''STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1.''; PubMed Europe PMC Scholia
  80. Shibasaki F, Price ER, Milan D, McKeon F.; ''Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4.''; PubMed Europe PMC Scholia
  81. Weng WK, Jarvis L, LeBien TW.; ''Signaling through CD19 activates Vav/mitogen-activated protein kinase pathway and induces formation of a CD19/Vav/phosphatidylinositol 3-kinase complex in human B cell precursors.''; PubMed Europe PMC Scholia
  82. Irish JM, Czerwinski DK, Nolan GP, Levy R.; ''Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry.''; PubMed Europe PMC Scholia
  83. Li CC, Dai RM, Longo DL.; ''Inactivation of NF-kappa B inhibitor I kappa B alpha: ubiquitin-dependent proteolysis and its degradation product.''; PubMed Europe PMC Scholia
  84. Garcia-Cozar FJ, Okamura H, Aramburu JF, Shaw KT, Pelletier L, Showalter R, Villafranca E, Rao A.; ''Two-site interaction of nuclear factor of activated T cells with activated calcineurin.''; PubMed Europe PMC Scholia
  85. Luo C, Shaw KT, Raghavan A, Aramburu J, Garcia-Cozar F, Perrino BA, Hogan PG, Rao A.; ''Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear import.''; PubMed Europe PMC Scholia
  86. Papp E, Tse JK, Ho H, Wang S, Shaw D, Lee S, Barnett J, Swinney DC, Bradshaw JM.; ''Steady state kinetics of spleen tyrosine kinase investigated by a real time fluorescence assay.''; PubMed Europe PMC Scholia
  87. Valentine MA, Bursten SL, Harris WE, Draves KE, Pollok BA, Ostrowski J, Bomsztyk K, Clark EA.; ''Generation of phosphatidic acid and diacylglycerols following ligation of surface immunoglobulin in human B lymphocytes: potential role in PKC activation.''; PubMed Europe PMC Scholia
  88. Cheng KT, Liu X, Ong HL, Swaim W, Ambudkar IS.; ''Local Ca²+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca²+ signals required for specific cell functions.''; PubMed Europe PMC Scholia
  89. Kochs G, Hummel R, Fiebich B, Sarre TF, Marmé D, Hug H.; ''Activation of purified human protein kinase C alpha and beta I isoenzymes in vitro by Ca2+, phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate.''; PubMed Europe PMC Scholia
  90. Park J, Yaseen NR, Hogan PG, Rao A, Sharma S.; ''Phosphorylation of the transcription factor NFATp inhibits its DNA binding activity in cyclosporin A-treated human B and T cells.''; PubMed Europe PMC Scholia
  91. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia
  92. Law CL, Aruffo A, Chandran KA, Doty RT, Clark EA.; ''Ig domains 1 and 2 of murine CD22 constitute the ligand-binding domain and bind multiple sialylated ligands expressed on B and T cells.''; PubMed Europe PMC Scholia
  93. Kim YJ, Sekiya F, Poulin B, Bae YS, Rhee SG.; ''Mechanism of B-cell receptor-induced phosphorylation and activation of phospholipase C-gamma2.''; PubMed Europe PMC Scholia
  94. Coughlin JJ, Stang SL, Dower NA, Stone JC.; ''RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling.''; PubMed Europe PMC Scholia
  95. Roifman CM, Wang G.; ''Phospholipase C-gamma 1 and phospholipase C-gamma 2 are substrates of the B cell antigen receptor associated protein tyrosine kinase.''; PubMed Europe PMC Scholia
  96. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF.; ''STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels.''; PubMed Europe PMC Scholia
  97. Fu C, Turck CW, Kurosaki T, Chan AC.; ''BLNK: a central linker protein in B cell activation.''; PubMed Europe PMC Scholia
  98. Chen Z, Hagler J, Palombella VJ, Melandri F, Scherer D, Ballard D, Maniatis T.; ''Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway.''; PubMed Europe PMC Scholia
  99. Su YW, Zhang Y, Schweikert J, Koretzky GA, Reth M, Wienands J.; ''Interaction of SLP adaptors with the SH2 domain of Tec family kinases.''; PubMed Europe PMC Scholia
  100. Park H, Wahl MI, Afar DE, Turck CW, Rawlings DJ, Tam C, Scharenberg AM, Kinet JP, Witte ON.; ''Regulation of Btk function by a major autophosphorylation site within the SH3 domain.''; PubMed Europe PMC Scholia
  101. Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMed Europe PMC Scholia
  102. Tanner MJ, Hanel W, Gaffen SL, Lin X.; ''CARMA1 coiled-coil domain is involved in the oligomerization and subcellular localization of CARMA1 and is required for T cell receptor-induced NF-kappaB activation.''; PubMed Europe PMC Scholia
  103. Suzuki H, Chiba T, Kobayashi M, Takeuchi M, Suzuki T, Ichiyama A, Ikenoue T, Omata M, Furuichi K, Tanaka K.; ''IkappaBalpha ubiquitination is catalyzed by an SCF-like complex containing Skp1, cullin-1, and two F-box/WD40-repeat proteins, betaTrCP1 and betaTrCP2.''; PubMed Europe PMC Scholia
  104. Meller N, Elitzur Y, Isakov N.; ''Protein kinase C-theta (PKCtheta) distribution analysis in hematopoietic cells: proliferating T cells exhibit high proportions of PKCtheta in the particulate fraction.''; PubMed Europe PMC Scholia
  105. Oellerich T, Bremes V, Neumann K, Bohnenberger H, Dittmann K, Hsiao HH, Engelke M, Schnyder T, Batista FD, Urlaub H, Wienands J.; ''The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85.''; PubMed Europe PMC Scholia
  106. Oellerich T, Grønborg M, Neumann K, Hsiao HH, Urlaub H, Wienands J.; ''SLP-65 phosphorylation dynamics reveals a functional basis for signal integration by receptor-proximal adaptor proteins.''; PubMed Europe PMC Scholia
  107. Brooks SR, Kirkham PM, Freeberg L, Carter RH.; ''Binding of cytoplasmic proteins to the CD19 intracellular domain is high affinity, competitive, and multimeric.''; PubMed Europe PMC Scholia
  108. Roifman CM, Ke S.; ''CD19 is a substrate of the antigen receptor-associated protein tyrosine kinase in human B cells.''; PubMed Europe PMC Scholia
  109. Clark MR, Friedrich RJ, Campbell KS, Cambier JC.; ''Human pre-B and B cell membrane mu-chains are noncovalently associated with a disulfide-linked complex containing a product of the B29 gene.''; PubMed Europe PMC Scholia
  110. Yamanashi Y, Kakiuchi T, Mizuguchi J, Yamamoto T, Toyoshima K.; ''Association of B cell antigen receptor with protein tyrosine kinase Lyn.''; PubMed Europe PMC Scholia
  111. Sundivakkam PC, Freichel M, Singh V, Yuan JP, Vogel SM, Flockerzi V, Malik AB, Tiruppathi C.; ''The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells.''; PubMed Europe PMC Scholia
  112. Zandi E, Chen Y, Karin M.; ''Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate.''; PubMed Europe PMC Scholia
  113. Coggeshall KM, McHugh JC, Altman A.; ''Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes.''; PubMed Europe PMC Scholia
  114. Teixeira C, Stang SL, Zheng Y, Beswick NS, Stone JC.; ''Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3.''; PubMed Europe PMC Scholia
  115. Dowler S, Montalvo L, Cantrell D, Morrice N, Alessi DR.; ''Phosphoinositide 3-kinase-dependent phosphorylation of the dual adaptor for phosphotyrosine and 3-phosphoinositides by the Src family of tyrosine kinase.''; PubMed Europe PMC Scholia
  116. Blasioli J, Paust S, Thomas ML.; ''Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22.''; PubMed Europe PMC Scholia
  117. Lorenzo PS, Kung JW, Bottorff DA, Garfield SH, Stone JC, Blumberg PM.; ''Phorbol esters modulate the Ras exchange factor RasGRP3.''; PubMed Europe PMC Scholia
  118. Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu JO, Ke H.; ''Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.''; PubMed Europe PMC Scholia
  119. Yamashita S, Mochizuki N, Ohba Y, Tobiume M, Okada Y, Sawa H, Nagashima K, Matsuda M.; ''CalDAG-GEFIII activation of Ras, R-ras, and Rap1.''; PubMed Europe PMC Scholia
  120. Leprince C, Draves KE, Geahlen RL, Ledbetter JA, Clark EA.; ''CD22 associates with the human surface IgM-B-cell antigen receptor complex.''; PubMed Europe PMC Scholia
  121. Ferguson KM, Kavran JM, Sankaran VG, Fournier E, Isakoff SJ, Skolnik EY, Lemmon MA.; ''Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.''; PubMed Europe PMC Scholia
  122. Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S.; ''Reconstitution of the B cell antigen receptor signaling components in COS cells.''; PubMed Europe PMC Scholia
  123. Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-García ME, Ovechkina YL, Rawlings DJ.; ''Phosphorylation of the CARMA1 linker controls NF-kappaB activation.''; PubMed Europe PMC Scholia
  124. Engels N, Wollscheid B, Wienands J.; ''Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha.''; PubMed Europe PMC Scholia
  125. Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM.; ''Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO.''; PubMed Europe PMC Scholia
  126. Kim LJ, Ferguson HA, Seto AG, Goodrich JA.; ''Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp.''; PubMed Europe PMC Scholia
  127. Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, Ho H, Wang S, Papp E, Bradshaw JM.; ''Molecular mechanism of the Syk activation switch.''; PubMed Europe PMC Scholia
  128. Rebhun JF, Castro AF, Quilliam LA.; ''Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction.''; PubMed Europe PMC Scholia
  129. Ozdener F, Dangelmaier C, Ashby B, Kunapuli SP, Daniel JL.; ''Activation of phospholipase Cgamma2 by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  130. Cheng KT, Liu X, Ong HL, Ambudkar IS.; ''Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels.''; PubMed Europe PMC Scholia
  131. Traenckner EB, Wilk S, Baeuerle PA.; ''A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B.''; PubMed Europe PMC Scholia
  132. Nore BF, Mattsson PT, Antonsson P, Bäckesjö CM, Westlund A, Lennartsson J, Hansson H, Löw P, Rönnstrand L, Smith CI.; ''Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases.''; PubMed Europe PMC Scholia
  133. Roifman CM, Mills GB, Stewart D, Cheung RK, Grinstein S, Gelfand EW.; ''Response of human B cells to different anti-immunoglobulin isotypes: absence of a correlation between early activation events and cell proliferation.''; PubMed Europe PMC Scholia
  134. Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, Siemasko K, Chan AC, Aebersold R, Clark MR.; ''The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways.''; PubMed Europe PMC Scholia
  135. Gold MR, Chan VW, Turck CW, DeFranco AL.; ''Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes.''; PubMed Europe PMC Scholia
  136. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMed Europe PMC Scholia
  137. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
  138. Rolli V, Gallwitz M, Wossning T, Flemming A, Schamel WW, Zürn C, Reth M.; ''Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop.''; PubMed Europe PMC Scholia
  139. Hanasaki K, Powell LD, Varki A.; ''Binding of human plasma sialoglycoproteins by the B cell-specific lectin CD22. Selective recognition of immunoglobulin M and haptoglobin.''; PubMed Europe PMC Scholia
  140. Nisitani S, Kato RM, Rawlings DJ, Witte ON, Wahl MI.; ''In situ detection of activated Bruton's tyrosine kinase in the Ig signaling complex by phosphopeptide-specific monoclonal antibodies.''; PubMed Europe PMC Scholia
  141. Kunkel HG.; ''Surface markers of human lymphocytes.''; PubMed Europe PMC Scholia
  142. Bohnenberger H, Oellerich T, Engelke M, Hsiao HH, Urlaub H, Wienands J.; ''Complex phosphorylation dynamics control the composition of the Syk interactome in B cells.''; PubMed Europe PMC Scholia
  143. Li Z, Nabel GJ.; ''A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription.''; PubMed Europe PMC Scholia
  144. Rodriguez R, Matsuda M, Perisic O, Bravo J, Paul A, Jones NP, Light Y, Swann K, Williams RL, Katan M.; ''Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.''; PubMed Europe PMC Scholia
  145. Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC.; ''BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.''; PubMed Europe PMC Scholia
  146. Alland L, Peseckis SM, Atherton RE, Berthiaume L, Resh MD.; ''Dual myristylation and palmitylation of Src family member p59fyn affects subcellular localization.''; PubMed Europe PMC Scholia
  147. Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT.; ''Inhibition of the B cell by CD22: a requirement for Lyn.''; PubMed Europe PMC Scholia
  148. Sanchez M, Misulovin Z, Burkhardt AL, Mahajan S, Costa T, Franke R, Bolen JB, Nussenzweig M.; ''Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.''; PubMed Europe PMC Scholia
  149. Wu C, Ghosh S.; ''beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta.''; PubMed Europe PMC Scholia
  150. Okamura H, Aramburu J, García-Rodríguez C, Viola JP, Raghavan A, Tahiliani M, Zhang X, Qin J, Hogan PG, Rao A.; ''Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity.''; PubMed Europe PMC Scholia
  151. Lin L, Czerwinski R, Kelleher K, Siegel MM, Wu P, Kriz R, Aulabaugh A, Stahl M.; ''Activation loop phosphorylation modulates Bruton's tyrosine kinase (Btk) kinase domain activity.''; PubMed Europe PMC Scholia
  152. Nel AE, Landreth GE, Goldschmidt-Clermont PJ, Tung HE, Galbraith RM.; ''Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin.''; PubMed Europe PMC Scholia
  153. Padeh S, Levitzki A, Gazit A, Mills GB, Roifman CM.; ''Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation.''; PubMed Europe PMC Scholia
  154. Roose JP, Mollenauer M, Ho M, Kurosaki T, Weiss A.; ''Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes.''; PubMed Europe PMC Scholia
  155. Han S, Collins BE, Bengtson P, Paulson JC.; ''Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking.''; PubMed Europe PMC Scholia
  156. Salim K, Bottomley MJ, Querfurth E, Zvelebil MJ, Gout I, Scaife R, Margolis RL, Gigg R, Smith CI, Driscoll PC, Waterfield MD, Panayotou G.; ''Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase.''; PubMed Europe PMC Scholia
  157. Wienands J, Schweikert J, Wollscheid B, Jumaa H, Nielsen PJ, Reth M.; ''SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation.''; PubMed Europe PMC Scholia
  158. Brezski RJ, Monroe JG.; ''B-cell receptor.''; PubMed Europe PMC Scholia
  159. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMed Europe PMC Scholia
  160. Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A.; ''Immunodeficiency in protein kinase cbeta-deficient mice.''; PubMed Europe PMC Scholia
  161. Burke JR, Wood MK, Ryseck RP, Walther S, Meyers CA.; ''Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2.''; PubMed Europe PMC Scholia
  162. Vasile S, Coligan JE, Yoshida M, Seon BK.; ''Isolation and chemical characterization of the human B29 and mb-1 proteins of the B cell antigen receptor complex.''; PubMed Europe PMC Scholia
  163. Wienands J, Hombach J, Radbruch A, Riesterer C, Reth M.; ''Molecular components of the B cell antigen receptor complex of class IgD differ partly from those of IgM.''; PubMed Europe PMC Scholia
  164. Fu C, Chan AC.; ''Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation.''; PubMed Europe PMC Scholia
  165. Roose JP, Mollenauer M, Gupta VA, Stone J, Weiss A.; ''A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells.''; PubMed Europe PMC Scholia
  166. Blank V, Kourilsky P, Israël A.; ''Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus.''; PubMed Europe PMC Scholia
  167. McConnell FM, Shears SB, Lane PJ, Scheibel MS, Clark EA.; ''Relationships between the degree of cross-linking of surface immunoglobulin and the associated inositol 1,4,5-trisphosphate and Ca2+ signals in human B cells.''; PubMed Europe PMC Scholia
  168. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
  169. Brooks SR, Li X, Volanakis EJ, Carter RH.; ''Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines.''; PubMed Europe PMC Scholia
  170. Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA, Kato RM, Kang S, Patrone L, Wall R, Teitell M, Leitges M, Kawakami T, Rawlings DJ.; ''PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling.''; PubMed Europe PMC Scholia

History

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112687
Reactome
view16:08, 9 October 2020ReactomeTeamReactome version 73
101604view11:47, 1 November 2018ReactomeTeamreactome version 66
101140view21:32, 31 October 2018ReactomeTeamreactome version 65
100668view20:06, 31 October 2018ReactomeTeamreactome version 64
100218view16:51, 31 October 2018ReactomeTeamreactome version 63
99769view15:17, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93934view13:46, 16 August 2017ReactomeTeamreactome version 61
93521view11:25, 9 August 2017ReactomeTeamreactome version 61
87188view08:07, 19 July 2016EgonwOntology Term : 'signaling pathway' added !
86619view09:22, 11 July 2016ReactomeTeamreactome version 56
83158view10:13, 18 November 2015ReactomeTeamVersion54
81511view13:03, 21 August 2015ReactomeTeamVersion53
76984view08:27, 17 July 2014ReactomeTeamFixed remaining interactions
76689view12:05, 16 July 2014ReactomeTeamFixed remaining interactions
76015view10:07, 11 June 2014ReactomeTeamRe-fixing comment source
75724view11:19, 10 June 2014ReactomeTeamReactome 48 Update
75074view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74860view17:46, 2 May 2014EgonwMarked two metabolites as a DataNode type="Metabolite"...
74721view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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Name  â†“Type  â†“Database reference  â†“Comment  â†“
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)ComplexR-HSA-1168601 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
ATPMetaboliteCHEBI:30616 (ChEBI)
Activated PKC betaComplexR-HSA-139829 (Reactome)
Active IKK complexComplexR-HSA-727820 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
Antigen R-ALL-173548 (Reactome)
Antigen R-ALL-983667 (Reactome)
Antigen:BCRComplexR-HSA-983689 (Reactome)
Antigen:p-BCR:SYKComplexR-HSA-983693 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:BTK:NCK1:VAV1:PLCG2ComplexR-HSA-9606167 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y223,Y551-BTK:NCK1:VAV1:PLCG2ComplexR-HSA-9606153 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y551-BTK:NCK1:VAV1:PLCG2ComplexR-HSA-9606149 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1ComplexR-HSA-983687 (Reactome)
Antigen:p-BCR:p-SYKComplexR-HSA-983690 (Reactome)
Antigen:p-BCRComplexR-HSA-983691 (Reactome)
AntigenR-ALL-983667 (Reactome)
BCAP SignalosomeComplexR-HSA-2045909 (Reactome)
BCRComplexR-HSA-983677 (Reactome)
BLNK (SLP-65) SignalosomeComplexR-HSA-984818 (Reactome)
BLNK ProteinQ8WV28 (Uniprot-TrEMBL)
BLNK:GRB2:SOS1:CIN85ComplexR-HSA-983692 (Reactome)
BTK ProteinQ06187 (Uniprot-TrEMBL)
BTKProteinQ06187 (Uniprot-TrEMBL)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CALM1 ProteinP0DP23 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP0DP23 (Uniprot-TrEMBL)
CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
CARMA1 oligomerComplexR-HSA-1169088 (Reactome)
CD19 ProteinP15391 (Uniprot-TrEMBL)
CD19 SignalosomeComplexR-HSA-2076233 (Reactome)
CD19:VAV1ComplexR-HSA-2076225 (Reactome)
CD22 ProteinP20273 (Uniprot-TrEMBL)
CD22:Antigen:p-BCRComplexR-HSA-5690660 (Reactome)
CD22ProteinP20273 (Uniprot-TrEMBL)
CD79A ProteinP11912 (Uniprot-TrEMBL)
CD79B ProteinP40259 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CHUK:IKBKB:IKBKGComplexR-HSA-168113 (Reactome) Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
CRAC channelComplexR-HSA-434679 (Reactome)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcineurin (CaN)ComplexR-HSA-2025977 (Reactome)
Calcineurin:Phosphorylated NFATC1,2,3ComplexR-HSA-2025899 (Reactome)
Cyclophilin A:Cyclosporin AComplexR-HSA-2026008 (Reactome)
Cyclosporin A MetaboliteCHEBI:4031 (ChEBI)
DAG MetaboliteCHEBI:17815 (ChEBI)
DAGMetaboliteCHEBI:17815 (ChEBI)
DAPP1ProteinQ9UN19 (Uniprot-TrEMBL)
Dephosphorylated NFATC1,2,3ComplexR-HSA-2025852 (Reactome)
FBXW11 ProteinQ9UKB1 (Uniprot-TrEMBL)
FKBP1A ProteinP62942 (Uniprot-TrEMBL)
FKBP1A:TacrolimusComplexR-HSA-2026019 (Reactome)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IGHD ProteinP01880 (Uniprot-TrEMBL)
IGHM ProteinP01871 (Uniprot-TrEMBL)
IGHV(1-?) ProteinA2KUC3 (Uniprot-TrEMBL)
IGHV1-2 ProteinP23083 (Uniprot-TrEMBL)
IGHV7-81(1-?) ProteinQ6PIL0 (Uniprot-TrEMBL)
IGKC ProteinP01834 (Uniprot-TrEMBL)
IGKV1-12 ProteinA0A0C4DH73 (Uniprot-TrEMBL)
IGKV1-5(23-?) ProteinP01602 (Uniprot-TrEMBL)
IGKV2-28 ProteinA0A075B6P5 (Uniprot-TrEMBL)
IGKV2D-30 ProteinA0A075B6S6 (Uniprot-TrEMBL)
IGKV3D-20 ProteinA0A0C4DH25 (Uniprot-TrEMBL)
IGKV4-1(21-?) ProteinP06312 (Uniprot-TrEMBL)
IGKVA18(21-?) ProteinA2NJV5 (Uniprot-TrEMBL)
IGLC1 ProteinP0CG04 (Uniprot-TrEMBL)
IGLC2 ProteinP0DOY2 (Uniprot-TrEMBL)
IGLC3 ProteinP0DOY3 (Uniprot-TrEMBL)
IGLC6 ProteinP0CF74 (Uniprot-TrEMBL)
IGLC7 ProteinA0M8Q6 (Uniprot-TrEMBL)
IGLV(23-?) ProteinA2NXD2 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
ITPR1 ProteinQ14643 (Uniprot-TrEMBL)
ITPR2 ProteinQ14571 (Uniprot-TrEMBL)
ITPR3 ProteinQ14573 (Uniprot-TrEMBL)
ITPR:I(1,4,5)P3 tetramerComplexR-HSA-169696 (Reactome)
Ig heavy chain V-I region EU ProteinP01742 (Uniprot-TrEMBL)
Ig heavy chain V-I region HG3 ProteinP01743 (Uniprot-TrEMBL)
Ig heavy chain V-II region ARH-77 ProteinP06331 (Uniprot-TrEMBL)
Ig heavy chain V-II region MCE ProteinP01817 (Uniprot-TrEMBL)
Ig heavy chain V-II region NEWM ProteinP01825 (Uniprot-TrEMBL)
Ig heavy chain V-II region OU ProteinP01814 (Uniprot-TrEMBL)
Ig heavy chain V-II region WAH ProteinP01824 (Uniprot-TrEMBL)
Ig heavy chain V-III region BRO ProteinP01766 (Uniprot-TrEMBL)
Ig heavy chain V-III region BUT ProteinP01767 (Uniprot-TrEMBL)
Ig heavy chain V-III region CAM ProteinP01768 (Uniprot-TrEMBL)
Ig heavy chain V-III region DOB ProteinP01782 (Uniprot-TrEMBL)
Ig heavy chain V-III region JON ProteinP01780 (Uniprot-TrEMBL)
Ig heavy chain V-III region KOL ProteinP01772 (Uniprot-TrEMBL)
Ig heavy chain V-III region TRO ProteinP01762 (Uniprot-TrEMBL)
Ig heavy chain V-III region WEA ProteinP01763 (Uniprot-TrEMBL)
Ig kappa chain V region EV15 ProteinP06315 (Uniprot-TrEMBL)
Ig kappa chain V-I region AG ProteinP01593 (Uniprot-TrEMBL)
Ig kappa chain V-I region AU ProteinP01594 (Uniprot-TrEMBL)
Ig kappa chain V-I region BAN ProteinP04430 (Uniprot-TrEMBL)
Ig kappa chain V-I region DEE ProteinP01597 (Uniprot-TrEMBL)
Ig kappa chain V-I region Daudi ProteinP04432 (Uniprot-TrEMBL)
Ig kappa chain V-I region Gal ProteinP01599 (Uniprot-TrEMBL)
Ig kappa chain V-I region HK101 ProteinP01601 (Uniprot-TrEMBL)
Ig kappa chain V-I region Wes ProteinP01611 (Uniprot-TrEMBL)
Ig kappa chain V-II region Cum ProteinP01614 (Uniprot-TrEMBL)
Ig kappa chain V-II region FR ProteinP01615 (Uniprot-TrEMBL)
Ig kappa chain V-II region RPMI 6410 ProteinP06310 (Uniprot-TrEMBL)
Ig kappa chain V-III region B6 ProteinP01619 (Uniprot-TrEMBL)
Ig kappa chain V-III region POM ProteinP01624 (Uniprot-TrEMBL)
Ig kappa chain V-III region VG ProteinP04433 (Uniprot-TrEMBL)
Ig lambda chain V region 4A ProteinP04211 (Uniprot-TrEMBL)
Ig lambda chain V-I region HA ProteinP01700 (Uniprot-TrEMBL)
Ig lambda chain V-I region NEW ProteinP01701 (Uniprot-TrEMBL)
Ig lambda chain V-I region NEWM ProteinP01703 (Uniprot-TrEMBL)
Ig lambda chain V-I region VOR ProteinP01699 (Uniprot-TrEMBL)
Ig lambda chain V-II region BOH ProteinP01706 (Uniprot-TrEMBL)
Ig lambda chain V-II region MGC ProteinP01709 (Uniprot-TrEMBL)
Ig lambda chain V-II region NEI ProteinP01705 (Uniprot-TrEMBL)
Ig lambda chain V-II region TOG ProteinP01704 (Uniprot-TrEMBL)
Ig lambda chain V-III region LOI ProteinP80748 (Uniprot-TrEMBL)
Ig lambda chain V-III region SH ProteinP01714 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Bau ProteinP01715 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Hil ProteinP01717 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Kern ProteinP01718 (Uniprot-TrEMBL)
Ig lambda chain V-VI region AR ProteinP01721 (Uniprot-TrEMBL)
IgH heavy chain V-III region VH26 precursor ProteinP01764 (Uniprot-TrEMBL)
LYN, p-SYKComplexR-HSA-9606888 (Reactome)
LYN,FYN,BLKComplexR-HSA-9606895 (Reactome)
MALT1 ProteinQ9UDY8 (Uniprot-TrEMBL)
MALT1ProteinQ9UDY8 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K7ProteinO43318 (Uniprot-TrEMBL)
MyrG2-BLK ProteinP51451 (Uniprot-TrEMBL)
MyrG2-PalmC3,6-FYN ProteinP06241 (Uniprot-TrEMBL)
MyrG2-PalmC3-LYN ProteinP07948 (Uniprot-TrEMBL)
MyrG2-PalmC3-LYNProteinP07948 (Uniprot-TrEMBL)
NAD+ MetaboliteCHEBI:57540 (ChEBI)
NAc-CD22 homo-oligomerR-HSA-5690698 (Reactome)
NAc-CD22ProteinP20273 (Uniprot-TrEMBL)
NCK1 ProteinP16333 (Uniprot-TrEMBL)
NCK1ProteinP16333 (Uniprot-TrEMBL)
NF-kappa-B p50,p65,c-Rel:IKBComplexR-HSA-1168593 (Reactome)
NF-kappa-B p50,p65,c-Rel:p-IKBComplexR-HSA-1168588 (Reactome)
NF-kappaB p50,p65,c-Rel dimerComplexR-HSA-1168598 (Reactome)
NF-kappaB p50,p65,c-Rel dimerComplexR-HSA-1168608 (Reactome)
NF-kappaB p50,p65,c-Rel:ub-p-IKBComplexR-HSA-1168613 (Reactome)
NF-kappaB:p-IkB:SCF-betaTrCPComplexR-HSA-1168617 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
NFKBIE ProteinO00221 (Uniprot-TrEMBL)
ORAI dimerComplexR-HSA-8862646 (Reactome)
ORAI1 ProteinQ96D31 (Uniprot-TrEMBL)
ORAI2 ProteinQ96SN7 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3CD:PIK3R1ComplexR-HSA-1806213 (Reactome)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PLCG2 ProteinP16885 (Uniprot-TrEMBL)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
PPIA ProteinP62937 (Uniprot-TrEMBL)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PRKCB ProteinP05771 (Uniprot-TrEMBL)
PRKCBProteinP05771 (Uniprot-TrEMBL)
PS MetaboliteCHEBI:18303 (ChEBI)
PSMetaboliteCHEBI:18303 (ChEBI)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRComplexR-HSA-5690677 (Reactome)
PTPN6ProteinP29350 (Uniprot-TrEMBL)
Phosphorylated NFATC1,2,3ComplexR-HSA-2025924 (Reactome)
RASGRP1 ProteinO95267 (Uniprot-TrEMBL)
RASGRP1,3ComplexR-HSA-1169462 (Reactome)
RASGRP3 ProteinQ8IV61 (Uniprot-TrEMBL)
REL ProteinQ04864 (Uniprot-TrEMBL)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
S-Farn-Me KRAS4B ProteinP01116-2 (Uniprot-TrEMBL)
S-Farn-Me PalmS NRAS ProteinP01111 (Uniprot-TrEMBL)
S-Farn-Me-2xPalmS HRAS ProteinP01112 (Uniprot-TrEMBL)
S-Farn-Me-PalmS KRAS4A ProteinP01116-1 (Uniprot-TrEMBL)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
STIM1 DimerComplexR-HSA-1168370 (Reactome)
STIM1 ProteinQ13586 (Uniprot-TrEMBL)
STIM1:CalciumComplexR-HSA-1168371 (Reactome)
STIM1:TRPC1ComplexR-HSA-2089954 (Reactome)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYKProteinP43405 (Uniprot-TrEMBL)
TRPC1 ProteinP48995 (Uniprot-TrEMBL)
TRPC1ProteinP48995 (Uniprot-TrEMBL)
Tacrolimus MetaboliteCHEBI:61049 (ChEBI)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-21,22-p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1ProteinP15498 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
p-12S-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-13S-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-14S-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-4Y-PIK3AP1 ProteinQ6ZUJ8 (Uniprot-TrEMBL)
p-4Y-PIK3AP1ProteinQ6ZUJ8 (Uniprot-TrEMBL)
p-5Y-BLNK ProteinQ8WV28 (Uniprot-TrEMBL)
p-6Y-CD19 ProteinP15391 (Uniprot-TrEMBL)
p-6Y-SYK ProteinP43405 (Uniprot-TrEMBL)
p-BCL10 ProteinO95999 (Uniprot-TrEMBL)
p-BCL10ProteinO95999 (Uniprot-TrEMBL)
p-CARMA1 OligomerComplexR-HSA-1168616 (Reactome) The coiled coil (CC) domain of CARMA1 interacts with the CC domain on other CARMA1 molecules to form oligomers of unknown stoichiometry.
p-CARMA1:MALT1:p-BCL10:TAK1:IKKComplexR-HSA-1168620 (Reactome) TAK1 and the IKK complex are observed to migrate to lipid rafts containing phosphorylated CARMA1, BCL10, and MALT1. By analogy with NF-kappaB signaling pathways in other cells, the CARMA1:BCL10MALT1:TAK1:IKK complex in B cells may also contain TAB1, TAB2 and/or TAB3, TRAF6.
p-CARMA1:MALT1:p-BCL10:TAK1ComplexR-HSA-1168619 (Reactome) TAK1 and the IKK complex are observed to migrate to lipid rafts containing phosphorylated CARMA1, BCL10, and MALT1. By analogy with NF-kappaB signaling pathways in other cells, the CARMA1:BCL10MALT1:TAK1:IKK complex in B cells may also contain TAB1, TAB2 and/or TAB3, TRAF6.
p-CARMA1:MALT1:p-BCL10ComplexR-HSA-1168622 (Reactome)
p-CD19:VAV1ComplexR-HSA-9606889 (Reactome)
p-RASGRP1,3:DAGComplexR-HSA-1168369 (Reactome) RasGRP3 binds diacylglycerol via its C1 domain.
p-S157,S161-NFKBIE ProteinO00221 (Uniprot-TrEMBL)
p-S157,S161-Ub-NFKBIE ProteinO00221 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S19,S23-NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
p-S19,S23-Ub-NFKBIB ProteinQ15653 (Uniprot-TrEMBL)
p-S243-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-S257-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-S265-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S559,S644,S652-CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
p-T133-RASGRP3 ProteinQ8IV61 (Uniprot-TrEMBL)
p-T184-RASGRP1 ProteinO95267 (Uniprot-TrEMBL)
p-Y139-DAPP1 ProteinQ9UN19 (Uniprot-TrEMBL)
p-Y139-DAPP1:PIP3ComplexR-HSA-1168366 (Reactome)
p-Y139-DAPP1:PLCG2:PIP3ComplexR-HSA-9606886 (Reactome)
p-Y188,Y199-CD79A ProteinP11912 (Uniprot-TrEMBL)
p-Y196,Y207-CD79B ProteinP40259 (Uniprot-TrEMBL) By homology with CD79A (Ig-alpha), CD79B (Ig-beta) is presumed to be phosphorylated on tyrosines 196 and 207.
p-Y223,Y551-BTK ProteinQ06187 (Uniprot-TrEMBL)
p-Y551-BTK ProteinQ06187 (Uniprot-TrEMBL)
p-Y753,Y759,Y1217-PLCG2 ProteinP16885 (Uniprot-TrEMBL)
p-Y762,807,822-CD22 ProteinP20273 (Uniprot-TrEMBL)
p-Y762,807,822-CD22:Antigen:p-BCRComplexR-HSA-5690689 (Reactome)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
Source  â†“Target  â†“Type  â†“Database reference  â†“Comment  â†“
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)ArrowR-HSA-1168643 (Reactome)
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)R-HSA-1168642 (Reactome)
26S proteasomemim-catalysisR-HSA-1168640 (Reactome)
ADPArrowR-HSA-1168374 (Reactome)
ADPArrowR-HSA-1168635 (Reactome)
ADPArrowR-HSA-1168638 (Reactome)
ADPArrowR-HSA-1168641 (Reactome)
ADPArrowR-HSA-5690702 (Reactome)
ADPArrowR-HSA-9606159 (Reactome)
ADPArrowR-HSA-9606162 (Reactome)
ADPArrowR-HSA-9606163 (Reactome)
ADPArrowR-HSA-9606883 (Reactome)
ADPArrowR-HSA-9606884 (Reactome)
ADPArrowR-HSA-983703 (Reactome)
ADPArrowR-HSA-983707 (Reactome)
ADPArrowR-HSA-983709 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
ATPR-HSA-1168374 (Reactome)
ATPR-HSA-1168635 (Reactome)
ATPR-HSA-1168638 (Reactome)
ATPR-HSA-1168641 (Reactome)
ATPR-HSA-5690702 (Reactome)
ATPR-HSA-9606159 (Reactome)
ATPR-HSA-9606162 (Reactome)
ATPR-HSA-9606163 (Reactome)
ATPR-HSA-9606883 (Reactome)
ATPR-HSA-9606884 (Reactome)
ATPR-HSA-983703 (Reactome)
ATPR-HSA-983707 (Reactome)
ATPR-HSA-983709 (Reactome)
Activated PKC betaArrowR-HSA-1168373 (Reactome)
Activated PKC betamim-catalysisR-HSA-1168635 (Reactome)
Active IKK complexArrowR-HSA-1168641 (Reactome)
Active IKK complexmim-catalysisR-HSA-1168638 (Reactome)
Antigen:BCRArrowR-HSA-983696 (Reactome)
Antigen:BCRR-HSA-983709 (Reactome)
Antigen:p-BCR:SYKArrowR-HSA-983700 (Reactome)
Antigen:p-BCR:SYKR-HSA-983707 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:BTK:NCK1:VAV1:PLCG2ArrowR-HSA-9606151 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:BTK:NCK1:VAV1:PLCG2R-HSA-9606163 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y223,Y551-BTK:NCK1:VAV1:PLCG2ArrowR-HSA-9606159 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y223,Y551-BTK:NCK1:VAV1:PLCG2R-HSA-9606162 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y223,Y551-BTK:NCK1:VAV1:PLCG2mim-catalysisR-HSA-9606162 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y551-BTK:NCK1:VAV1:PLCG2ArrowR-HSA-9606163 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y551-BTK:NCK1:VAV1:PLCG2R-HSA-9606159 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1:p-Y551-BTK:NCK1:VAV1:PLCG2mim-catalysisR-HSA-9606159 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1ArrowR-HSA-983703 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1R-HSA-9606151 (Reactome)
Antigen:p-BCR:p-SYKArrowR-HSA-983707 (Reactome)
Antigen:p-BCR:p-SYKR-HSA-983703 (Reactome)
Antigen:p-BCR:p-SYKmim-catalysisR-HSA-983703 (Reactome)
Antigen:p-BCR:p-SYKmim-catalysisR-HSA-983707 (Reactome)
Antigen:p-BCRArrowR-HSA-983709 (Reactome)
Antigen:p-BCRR-HSA-5690740 (Reactome)
Antigen:p-BCRR-HSA-983700 (Reactome)
AntigenR-HSA-983696 (Reactome)
BCAP SignalosomeArrowR-HSA-9606160 (Reactome)
BCAP Signalosomemim-catalysisR-HSA-2045911 (Reactome)
BCRR-HSA-983696 (Reactome)
BLNK (SLP-65) SignalosomeArrowR-HSA-9606162 (Reactome)
BLNK (SLP-65) Signalosomemim-catalysisR-HSA-1112666 (Reactome)
BLNK:GRB2:SOS1:CIN85R-HSA-983703 (Reactome)
BTKR-HSA-9606151 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+R-HSA-2025890 (Reactome)
CALM1R-HSA-74448 (Reactome)
CARMA1 oligomerR-HSA-1168635 (Reactome)
CD19 SignalosomeArrowR-HSA-9606887 (Reactome)
CD19 Signalosomemim-catalysisR-HSA-2076220 (Reactome)
CD19:VAV1R-HSA-9606883 (Reactome)
CD22:Antigen:p-BCRArrowR-HSA-5690740 (Reactome)
CD22:Antigen:p-BCRR-HSA-5690702 (Reactome)
CD22R-HSA-5690740 (Reactome)
CHUK:IKBKB:IKBKGR-HSA-1168637 (Reactome)
CRAC channelArrowR-HSA-434700 (Reactome)
CRAC channelmim-catalysisR-HSA-434798 (Reactome)
Ca2+ArrowR-HSA-1168376 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+ArrowR-HSA-2089943 (Reactome)
Ca2+ArrowR-HSA-434798 (Reactome)
Ca2+R-HSA-1168373 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-2025890 (Reactome)
Ca2+R-HSA-2089943 (Reactome)
Ca2+R-HSA-434798 (Reactome)
Ca2+R-HSA-74448 (Reactome)
Calcineurin (CaN)R-HSA-2025890 (Reactome)
Calcineurin:Phosphorylated NFATC1,2,3ArrowR-HSA-2025890 (Reactome)
Calcineurin:Phosphorylated NFATC1,2,3R-HSA-2025882 (Reactome)
Calcineurin:Phosphorylated NFATC1,2,3mim-catalysisR-HSA-2025882 (Reactome)
Cyclophilin A:Cyclosporin ATBarR-HSA-2025882 (Reactome)
DAGArrowR-HSA-1112666 (Reactome)
DAGR-HSA-1168373 (Reactome)
DAGR-HSA-1168374 (Reactome)
DAPP1R-HSA-9606884 (Reactome)
Dephosphorylated NFATC1,2,3ArrowR-HSA-2025882 (Reactome)
FKBP1A:TacrolimusTBarR-HSA-2025882 (Reactome)
GDPArrowR-HSA-1168636 (Reactome)
GRB2-1R-HSA-9606887 (Reactome)
GTPR-HSA-1168636 (Reactome)
I(1,4,5)P3ArrowR-HSA-1112666 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
IP3 receptor homotetramerR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramerArrowR-HSA-169680 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-1168376 (Reactome)
ITPR:I(1,4,5)P3 tetramermim-catalysisR-HSA-169683 (Reactome)
LYN, p-SYKmim-catalysisR-HSA-9606163 (Reactome)
LYN,FYN,BLKmim-catalysisR-HSA-983709 (Reactome)
MALT1R-HSA-1168644 (Reactome)
MAP3K7R-HSA-1168637 (Reactome)
MyrG2-PalmC3-LYNmim-catalysisR-HSA-5690702 (Reactome)
NAc-CD22 homo-oligomerArrowR-HSA-5690669 (Reactome)
NAc-CD22R-HSA-5690669 (Reactome)
NCK1R-HSA-9606151 (Reactome)
NF-kappa-B p50,p65,c-Rel:IKBR-HSA-1168638 (Reactome)
NF-kappa-B p50,p65,c-Rel:p-IKBArrowR-HSA-1168638 (Reactome)
NF-kappa-B p50,p65,c-Rel:p-IKBR-HSA-1168642 (Reactome)
NF-kappaB p50,p65,c-Rel dimerArrowR-HSA-1168633 (Reactome)
NF-kappaB p50,p65,c-Rel dimerArrowR-HSA-1168640 (Reactome)
NF-kappaB p50,p65,c-Rel dimerR-HSA-1168633 (Reactome)
NF-kappaB p50,p65,c-Rel:ub-p-IKBArrowR-HSA-1168643 (Reactome)
NF-kappaB p50,p65,c-Rel:ub-p-IKBR-HSA-1168640 (Reactome)
NF-kappaB:p-IkB:SCF-betaTrCPArrowR-HSA-1168642 (Reactome)
NF-kappaB:p-IkB:SCF-betaTrCPR-HSA-1168643 (Reactome)
ORAI dimerR-HSA-434700 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2045911 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2076220 (Reactome)
PI(3,4,5)P3R-HSA-9606151 (Reactome)
PI(3,4,5)P3R-HSA-9606884 (Reactome)
PI(4,5)P2R-HSA-1112666 (Reactome)
PI(4,5)P2R-HSA-2045911 (Reactome)
PI(4,5)P2R-HSA-2076220 (Reactome)
PIK3CD:PIK3R1R-HSA-9606160 (Reactome)
PIK3CD:PIK3R1R-HSA-9606887 (Reactome)
PLCG2R-HSA-9606151 (Reactome)
PLCG2R-HSA-9606894 (Reactome)
PRKCBR-HSA-1168373 (Reactome)
PSR-HSA-1168373 (Reactome)
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRArrowR-HSA-5690701 (Reactome)
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRTBarR-HSA-983707 (Reactome)
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRTBarR-HSA-983709 (Reactome)
PTPN6R-HSA-5690701 (Reactome)
Phosphorylated NFATC1,2,3R-HSA-2025890 (Reactome)
R-HSA-1112666 (Reactome) Phospholipase C gamma (PLC-gamma) is activated by phosphorylation in response to antigen-binding by the B cell receptor (Carter et al. 1991, Roitman and Wang 1992, Rodriguez et al. 2001, Kim et al. 2004, Sekiya et al. 2004). Phospholipase C gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate and diacylglycerol (Carter et al. 1991, Kim et al. 2004). Human B cells contain both PLC-gamma1 and PLC-gamma2, with PLC-gamma2 predominating (Coggeshall et al. 1992).
R-HSA-1168373 (Reactome) Human Protein kinase C beta (PKC-beta) is activated by calcium ions, diacylglycerol, and binds phosphatidylserine (Kochs et al. 1991). Experiments in mice have shown that knocking out PKC-beta causes severe defects in B cells, leading to the conclusion that PKC-beta is the predominant signaling PKC in these cells (Leitges et al. 1996, Su et al. 2002, Saijo et al. 2002).
R-HSA-1168374 (Reactome) RasGRP1 and RasGRP3 translocate to the plasma membrane where they bind diacylglycerol (Lorenzo et al. 2001) and are phosphorylated (Teixeira et al. 2003, Zheng et al. 2005). Though RasGRP3 is phosphorylated in vitro and in some cell lines (e.g. Ramos cells) by protein kinase C theta (PKC-theta, Zheng et al. 2005), normal B cells do not contain PKC-theta (Meller et al. 1999). Both Rasgrp1 and Rasgrp3 participate in activating Ras in response to BCR signaling in mouse B cells (Coughlin et al. 2005).
R-HSA-1168376 (Reactome) In the resting state the luminal domain of STIM1 binds Ca2+ ions within the endoplasmic reticulum and this binding prevents dimerization of STIM1 (Luik et al. 2008). Upon depletion of Ca2+ ions from the endoplasmic reticulum, STIM1 is no longer bound to Ca2+ and forms homodimers (Muik et al. 2008, Luik et al. 2008, Park et al. 2009).
R-HSA-1168633 (Reactome) Nf-kappaB subunits contain nuclear localization sequences and, in the absence of IkB, are translocated to the nucleus (Bauerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008). c-Rel binds to importins alpha5, alpha6, and alpha7; RelB binds to importins alpha5 and alpha6; p52 binds importin alpha3, alpha4, alpha5, and alpha6 (Fagerlund et al. 2008)
R-HSA-1168635 (Reactome) CARMA1 is phosphorylated at serines 559, 644, and 652 by Protein Kinase C beta (PKC-beta) (Sommer et al. 2005). CARMA1 is constitutively oligomerized (Tanner et al. 2007) and most CARMA1 in unstimulated cells is cytosolic (Sommer et al. 2005, Tanner et al. 2007), though a portion is constitutively associated with the plasma membrane (Gaide et al. 2002, Sommer et al. 2005). After phosphorylation, CARMA1 is associated with lipid rafts in the plasma membrane (Sommer et al. 2005). Note that some publications refer to CARMA1 with a different N-terminal methionine that is 7 amino acids shorter. In this case the phosphorylated serines are 552, 537, and 645.
R-HSA-1168636 (Reactome) RasGRP1 (Roose et al. 2007) and RasGRP3 (Ohba et al. 2000, Yamashita et al. 2000, Rebhun et al. 2000, Lorenzo et al. 2001) catalyze the exchange of GDP for GTP bound by RAS.
R-HSA-1168637 (Reactome) TAK1 and the IKK complex are observed to migrate from the cytosol to lipid rafts containing the CARMA1:BCL10:MALT1 (CBM) complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). By analogy with activation of NF-KappaB signaling in T cells, TAK1 in B cells may also be bound to TAB1 and TAB2 or TAB3, which bind K63-conjugated polyubiquitin on a TRAF protein bound to the CBM complex (reviewed in Shinohara et al. 2009).
R-HSA-1168638 (Reactome) Activated IKK complex phosphorylates the I-kappaB component of the cytoplasmic NF-kappaB complex (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999). B cells contain I-kappaB-alpha, I-kappaB-beta, and I-kappaB-epsilon (Whiteside et al. 1997, Li and Nabel 1997).
R-HSA-1168640 (Reactome) Phosphorylated, ubiquitinated IkB is degraded by the proteasome (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). IkB does not dissociate from NF-kB before it is proteolyzed (Miyamoto et al. 1994, Traenckner et al. 1994, DiDonato et al. 1995, Lin et al. 1995).
R-HSA-1168641 (Reactome) TAK1 phosphorylates IKK-beta (Wang et al. 2001). As inferred from chicken B cells, the reaction in human B cells may occur when TAK1 and the IKK complex are associated with the CARMA1:BCL10:MALT1 (CBM) complex. During T cell activation TAK1 forms a complex with TAB1 and TAB2, which binds K-63 conjugated polyubiquitin attached to TRAF6 associated with the CBM complex (Sun et al. 2004, reviewed in Shinohara et al. 2009). TRAF6 also polyubiquitinates IKK-gamma in T cells (Zhou et al. 2004). B cells contain functional TRAF6 and TRAF2 (Zhang et al. 2010) so the same mechanism may occur during activation of B cells.
R-HSA-1168642 (Reactome) SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) bind IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999).
R-HSA-1168643 (Reactome) SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) catalyze the polyubiquitination of IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999).
R-HSA-1168644 (Reactome) CARMA1 is phosphorylated and recruits BCL10 and MALT1 to the plasma membrane to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007). Evidence from T cells (Jurkat cells) indicates that MALT1 and BCL10 oligomerize to activate the IKK complex (Zhou 2004).
R-HSA-169680 (Reactome) The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
R-HSA-169683 (Reactome) IP3 promotes the release of intracellular calcium.
R-HSA-2025882 (Reactome) As inferred from mouse (Okamura et al. 2000), calcineurin dephosphorylates NFATC2 at 13 serine residues (Batiuk et al. 1997, Kim et al. 2000). B lymphocytes also contain NFATC2 and NFATC3 which are inferred to undergo dephosphorylation at homologous serines. Dephosphorylation of NFATs exposes a nuclear localization signal which cause NFATs to be imported into the nucleus (Kim et al. 2000). In mouse, Calcineurin is observed to also transit into the nucleus in a complex with NFATs and may remain associated (Shibasaki et al. 1996).
R-HSA-2025890 (Reactome) Calcium activates calcineurin in two ways: binding the regulatory subunit of calcineurin directly and binding calmodulin which then interacts with the catalytic subunit of calcineurin. As inferred from mouse, B lymphocytes contain the R1 regulatory subunit (PPP3R1) and the beta catalytic subunit (PPP3CB).
In the presence of calcium and calcium:calmodulin calcineurin binds phosphorylated and unphosphorylated NFATs at 2 regions in the N-terminus (Luo et al. 1996, Garcia-Cozar et al. 1998, Park et al. 2000, evidence from mouse in Loh et al. 1996 and Wesselborg et al. 1996). Calcineurin also weakly interacts with NFATs in the absence of calcium (Garcia-Cozar et al. 1998).
R-HSA-2045911 (Reactome) PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992, Chantry et al. 1997). Experiments in mice indicate that PI3K associated with BCAP is partly responsible for the activity (Aiba et al. 2008). (PI3K associated with CD19 is also partly responsible (Aiba et al. 2008).)
R-HSA-2076220 (Reactome) PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992). Experiments in mice indicate that PI3K associated with CD19 is partly responsible for the activity (Buhl et al. 1997, Otero et al. 2001, Aiba et al. 2008). (PI3K associated with BCAP is also partly responsible (Aiba et al. 2008).)
R-HSA-2089927 (Reactome) The polybasic region of STIM1 interacts with 2 aspartate residues in the C-terminal region of TRPC1 (Zeng et al. 2008, Huang et al. 2006). The STIM1:TRPC1 complex can form a tenary complex with ORAI1 (Ong et al. 2007, Jardin et al. 2008) and ORAI participates in function of STIM1:TRPC1 channels (Cheng et al. 2008, Cheng et al. 2011). As inferred from chicken DT40 cells, TRPC1 (and possibly other TRP channels) participates in store-operated calcium influx during signaling by the B cell receptor (Mori et al. 2002).
R-HSA-2089943 (Reactome) TRPC1 forms a channel that transports Ca2+ across the plasma membrane. TRPC1 is gated by STIM1 (Ong et al. 2007).
R-HSA-434700 (Reactome) Sustained calcium signalling in lymphocytes and platelets requires the uptake of extracellular calcium when intracellular stores are depleted. The process whereby intracellular calcium depletion stimulates calcium uptake is often referred to as Store-operated calcium entry (SOCE). Store depletion is sensed by stromal interaction molecule 1 (STIM1), which then translocates to the plasma membrane and associates with 2 dimers of Orai to form a calcium-release activated calcium (CRAC) channel.
R-HSA-434798 (Reactome) Activation of Calcium-release-activated (CRAC) channels allows influx of calcium. The Orai component of CRAC is responsible for the selectivity of the channel, while the Stim component is responsible for activation.
R-HSA-5690669 (Reactome) In resting B cells, CD22 is a prominent cis ligand for itself, forming CD22 homo-oligomers. Cross-linking experiments showed that CD22 primarily recognizes alpha2,6-linked sialic acid (2,6Sia or N-acetylneuraminic acid (NAc)) on neighboring CD22 molecules present on the same B-cell (Han et al. 2005). NH2-terminal immuno globulin (Ig) domains, Ig1 and Ig2, mediate 2,6Sia binding (Law et al. 1998, Jin et al. 2002). Thus, CD22 recognizes self structures and triggers inhibitory signals, which may be relevant for suppression of autoimmune B-cell responses.
R-HSA-5690701 (Reactome) The phosphorylated ITIMs of CD22 facilitates recruitment of the tyrosine phosphatase SHP1 (Src homology region 2 domain-containing phosphatase-1 also referred as PTPN6/Tyrosine-protein phosphatase non-receptor type 6), which down modulates BCR signalling (Doody et al. 1995). Activation of SHP1 regulates the strength of the BCR-induced Ca+2 signal. Regulation of Ca+2 signalling occurs both by dephosphorylation of intracellular SHP1 substrates which are important for triggering of Ca+2 signals (Adachi et al. 2001, Stebbins et al. 2003), as well as by a SHP1 dependent activation of the Ca+2 plasma membrane pump PMCA4 which controls termination of the signal (Muller et al. 2013, Ghosh et al. 2006).
R-HSA-5690702 (Reactome) After ligation of membrane-bound IgM, CD22 is quickly tyrosine phosphorylated on its cytoplasmic ITIM sequence (immunoreceptor tyrosine-based inhibition motif). The tyrosine kinase involved in CD22 phosphorylation is LYN, a member of the Src kinase family (Smith et al. 1998). The CD22 cytoplasmic tail contains six tyrosines, three of which belong to the ITIM sequence (Nitschke & Tsubata 2004).
R-HSA-5690740 (Reactome) Physical association of CD22 with the BCR seems to have direct involvement in the regulation of BCR signalling, as antibody-mediated clustering of CD22 with the BCR leads to dampened signaling (Smith et al. 1998), and evidence of their association has been obtained by confocal microscopy, coimmunoprecipitation and chemical crossing (Zhang et al. 2004, Phee et al. 2001, Peaker et al. 1993, Law et al. 1994, Leprince et al. 1993, Collins et al. 2006). Forced ligation of CD22 to the BCR dramatically increases CD22 phosphorylation and suppression of BCR signalling (Macauley, 2013). This is relevant to suppression of BCR signalling to membrane antigens on B cells that contain self sialic acids (Lanoue, 2002; Macauley 2013). CD22 ligand binding modulates its activity as a negative regulator of B cell signalling.
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions (Crouch and Klee 1980).
R-HSA-9606151 (Reactome) Phosphorylated BLNK (also called BASH or SLP-65) at the plasma membrane recruits BTK, PLC gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Wienands et al. 1998, Su et al. 1999, Baba et al. 2001, Chiu et al. 2002). The SH2 domain of BTK binds phosphorylated BLNK (Hashimoto et al. 1999, Su et al. 1999, Baba et al. 2001). BLNK is constitutively bound to CIN85 and phosphorylated BLNK is bound to a large complex containing CIN85, SOS1, GRB2, phosphorylated SYK, and the B cell receptor.
R-HSA-9606159 (Reactome) After phosphorylation on tyrosine-551 by LYN or SYK, BTK autophosphorylates tyrosine-223 (Wahl et al. 1997, Nore et al. 2003, and inferred from mouse homologs). Maximum autophosphorylation occurs 5 minutes after activation of the B cell receptor and returns to low phosphorylation after 30 minutes (Nisitani et al. 1999).
R-HSA-9606160 (Reactome) Phosphorylated PIK3AP1 (BCAP) binds the p85 subunit of phosphoinositide 3-kinase (PI3K) (inferred from chicken homologs). PIK3AP1 is phosphorylated by LYN in response to activation of CD19.
R-HSA-9606162 (Reactome) Activated BTK (BTK phosphorylated on tyrosine-551 and tyrosine-223) bound to phosphorylated BLNK phosphorylates phospholipase gamma-2 (PKCG2) on tyrosines 753, 759, and 1217 (Rodriguez et al. 2001 and inferred from the rat homolog) thereby activating PLCG2 to hydrolyze phosphatidylinositol 4,5-bisphosphate, yielding the second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). PLCG2 also binds phosphoinositol 3,4,5-trisphosphate (PIP3) produced by PI3K at the plasma membrane.
R-HSA-9606163 (Reactome) LYN and activated (phosphorylated) SYK phosphorylate BTK (Baba et al. 2001, Lin et al. 2009, also inferred from chicken homologs and mouse homologs) after BTK is recruited to the plasma membrane by phosphorylated BLNK (Baba et al. 2001) and phosphoinositol 3,4,5-trisphosphate (PIP3) (Salim et al. 1996). Phosphorylation of tyrosine-551 occurs within 30 seconds of B cell receptor activation and returns to low phosphorylation after 30 minutes (Nisitani et al. 1999).
R-HSA-9606883 (Reactome) In response to BCR activation, CD19 in a stable complex with VAV1 is phosphorylated by Src kinases (Chalupny et al. 1993, inferred from mouse homologs in Xu et al. 2002), one of which may be LYN (inferred from mouse homologs).
R-HSA-9606884 (Reactome) DAPP1 (BAM32) is recruited to the plasma membrane by the binding of its PH domain to phosphoinositol 3,4,5-trisphosphate (PIP3) (Dowler et al. 1999, Marshall et al. 2000, Ferguson et al. 2000). DAPP1 also binds phosphatidylinositol 3,4-bisphosphate (Dowler et al. 1999, Ferguson et al. 2000) and therefore remains bound at the plasma membrane after PIP3 has been dephosphorylated by phosphatases. At the plasma membrane DAPP1 is phosphorylated by a Src family kinase, likely LYN in B cells (Dowler et al. 2000).
R-HSA-9606887 (Reactome) Phosphorylated CD19 binds PI3K (Roifman and Ke 1993, Chalupny et al. 1993, Uckun et al. 1993, Weng et al. 1994, Brooks et al. 2000, Brooks et al. 2004) and can bind PLC-gamma2 (PLCG2), which competes with VAV1 for the binding to phosphotyrosine-391 on CD19 (Brooks et al. 2000, Brooks et al. 2004). GRB2 appears to bind phosphotyrosine-330 on CD19 (Brooks et al. 2004).
R-HSA-9606894 (Reactome) Phosphorylated DAPP1 (BAM32) bound to phosphoinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane binds phospholipase gamma-2 (PLCG2) (Marshall et al. 2000).
R-HSA-983696 (Reactome) Mature, unstimulated B cells express IgM and IgD immunoglobulins on their surfaces (Fu et al. 1974, Fu et al. 1975, reviewed in Kunkel 1975). The immunoglobulins form B cell receptor (BCR) complexes with disulfide-linked heterodimers of Ig-alpha (CD79A) and Ig-beta (CD79B), which have cytoplasmic tails containing immunoreceptor tyrosine-based activation motifs (ITAMs) (van Noesel et al. 1992, Saouaf et al. 1995, inferred from mouse Hombach et al. 1990, Wienands et al. 1990). Upon binding of antigen to the immunoglobulin a chain of phosphorylation events is triggered (Nel et al. 1984, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Harwood and Batista 2010).
R-HSA-983700 (Reactome) The SYK protein tyrosine kinase binds specifically to phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Law et al. 1994, Saouaf et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding activates the kinase activity of SYK (Rowley et al. 1995, Tsang et al. 2008).
R-HSA-983703 (Reactome) BLNK (SLP-65, BASH) forms a stable complex with GRB2, SOS1, and CIN85 in the cytosol. The complex is recruited to the plasma membrane where activated (phosphorylated) SYK phosphorylates BLNK at tyrosines 72, 84, 96, 178, and 189 (Fu et al. 1998, Chiu et al. 2002, inferred from mouse in Wienands et al. 1998, from chicken in Oellerich et al. 2009). Phosphorylated BLNK serves as a scaffold that binds effector molecules such as Phospholipase C. As inferred from mouse, BLNK interacts with phosphorylated tyrosines on CD79A (Ig-alpha) (Engels et al. 2001, Kabak et al. 2002).
R-HSA-983707 (Reactome) The SYK protein tyrosine kinase autophosphorylates at tyrosines 131, 323, 348, 352, 525, and 526 (Law et al. 1994, Rowley et al. 1995, Baldock et al. 2000, Irish et al. 2006, Papp et al. 2007, Chen et al. 2008, Tsang et al. 2008). The autophosphorylation increases the kinase activity of SYK. SYK is also phosporylated on additional residues in response to BCR activation (Bohnenberger et al. 2011).
R-HSA-983709 (Reactome) The B cell receptor (BCR) comprises an immunoglobulin complexed with a heterodimer of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29). After immunoglobulin IgM or IgD binds antigen the associated Ig-alpha and Ig-beta are each observed to be phosphorylated at two tyrosine residues in the cytoplasmic immunoreceptor tyrosine-activated motif (ITAM) (Sanchez et al. 1993, Hata et al. 1994, Saouaf et al. 1994, Saouaf et al. 1995). Saouaf et al. (1995) showed that the kinase Blk could phosphorylate both tyrosines of each ITAM and that the kinase SYK specifically bound phosphorylated but not unphosphorylated ITAMs. In mouse the kinase Lyn and other kinases phosphorylate one tyrosine and Syk is believed to phosphorylate the other (Yamanashi et al. 1991, Flaswinkel and Reth 1994, Rolli et al. 2002).
RASGRP1,3R-HSA-1168374 (Reactome)
STIM1 DimerArrowR-HSA-1168376 (Reactome)
STIM1 DimerR-HSA-2089927 (Reactome)
STIM1 DimerR-HSA-434700 (Reactome)
STIM1:CalciumR-HSA-1168376 (Reactome)
STIM1:TRPC1ArrowR-HSA-2089927 (Reactome)
STIM1:TRPC1mim-catalysisR-HSA-2089943 (Reactome)
SYKR-HSA-983700 (Reactome)
TRPC1R-HSA-2089927 (Reactome)
UbR-HSA-1168643 (Reactome)
VAV1R-HSA-9606151 (Reactome)
p-4Y-PIK3AP1R-HSA-9606160 (Reactome)
p-BCL10R-HSA-1168644 (Reactome)
p-CARMA1 OligomerArrowR-HSA-1168635 (Reactome)
p-CARMA1 OligomerR-HSA-1168644 (Reactome)
p-CARMA1:MALT1:p-BCL10:TAK1:IKKArrowR-HSA-1168637 (Reactome)
p-CARMA1:MALT1:p-BCL10:TAK1:IKKR-HSA-1168641 (Reactome)
p-CARMA1:MALT1:p-BCL10:TAK1:IKKmim-catalysisR-HSA-1168641 (Reactome)
p-CARMA1:MALT1:p-BCL10:TAK1ArrowR-HSA-1168641 (Reactome)
p-CARMA1:MALT1:p-BCL10ArrowR-HSA-1168644 (Reactome)
p-CARMA1:MALT1:p-BCL10R-HSA-1168637 (Reactome)
p-CD19:VAV1ArrowR-HSA-9606883 (Reactome)
p-CD19:VAV1R-HSA-9606887 (Reactome)
p-RASGRP1,3:DAGArrowR-HSA-1168374 (Reactome)
p-RASGRP1,3:DAGmim-catalysisR-HSA-1168636 (Reactome)
p-Y139-DAPP1:PIP3ArrowR-HSA-9606884 (Reactome)
p-Y139-DAPP1:PIP3R-HSA-9606894 (Reactome)
p-Y139-DAPP1:PLCG2:PIP3ArrowR-HSA-9606894 (Reactome)
p-Y762,807,822-CD22:Antigen:p-BCRArrowR-HSA-5690702 (Reactome)
p-Y762,807,822-CD22:Antigen:p-BCRR-HSA-5690701 (Reactome)
p21 RAS:GDPR-HSA-1168636 (Reactome)
p21 RAS:GTPArrowR-HSA-1168636 (Reactome)
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