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

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6, 11, 17, 40, 44...7, 14, 30, 50, 70...6, 27, 92, 134, 14016, 21, 33, 43, 10345, 145, 150, 156, 1576, 24, 134114, 121, 137, 1482, 31, 99, 132, 13815, 33, 81, 123, 1603, 23, 28, 42, 65...4, 60, 74, 104, 112...25, 35, 101, 126, 152...8818, 91, 106, 109, 129...26, 36, 77, 83, 12455, 64, 66, 16611, 100, 116, 154, 162...2, 31, 1385, 29, 85, 8740, 54, 69, 79, 89...2413, 62, 127, 14717, 59, 6725, 35, 101, 126, 152...19, 72, 1179, 17, 59, 6757, 105, 133, 13948, 108, 1511, 8, 55, 56, 58...24, 27, 4112, 39, 49, 57, 78...10, 22, 32, 34, 38...nucleoplasmcytosolendoplasmic reticulum lumenplasma membraneCyclosporin A p-4Y-PIK3AP1 CD22 Ig heavy chain V-III region JON PRKCBPSMB9 MAP3K7 IGHV1-2 Ig lambda chain V-I region NEW IGHV(1-?) Ig lambda chain V-II region NEI IGKV1-5(23-?) PS Ig heavy chain V-I region HG3 Ig lambda chain V-I region NEWM Ig kappa chain V-III region B6 ATPAntigen Ig kappa chain V-III region VG Ig heavy chain V-I region EU Ig kappa chain V-III region POM Ig kappa chain V-I region DEE Ig lambda chain V-VI region AR PSME2 IGKV2D-30 IGKC Ig kappa chain V-I region BAN Antigen:p-BCR:SYKIGHV7-81(1-?) Ig kappa chain V-I region HK101 Ig lambda chain V-VI region AR IgH heavy chain V-III region VH26 precursor p-Y188,Y199-CD79A Ig lambda chain V-II region MGC Ig heavy chain V-III region BRO Ig lambda chain V-II region BOH Ig kappa chain V-I region Gal MALT1Activated PKC betaTacrolimus Ig heavy chain V-III region KOL IGLC3 Ig heavy chain V-III region BUT Ig lambda chain V-II region BOH REL Ig kappa chain V-I region BAN Ig lambda chain V-II region TOG DAG ITPR1 p21 RAS:GTPIgH heavy chain V-III region VH26 precursor ORAI1 IGKV1-12 PPP3CA AntigenIg kappa chain V-I region AG p-Y196,Y207-CD79B Ig heavy chain V-III region BUT SH3KBP1 Ig kappa chain V-III region B6 Ig heavy chain V-II region WAH PPP3CB Ig heavy chain V-III region JON Ig heavy chain V-III region CAM Ig heavy chain V-II region MCE Ig heavy chain V-II region ARH-77 Ig heavy chain V-I region EU Ig lambda chain V-IV region Bau GTP IGHD p-Y188,Y199-CD79A Ig kappa chain V-I region DEE IGLV(23-?) Ig lambda chain V-III region LOI IGLC7 Ig heavy chain V-II region WAH PSMA5 PSMD7 Ig kappa chain V-I region DEE Ig kappa chain V-III region VG Ig heavy chain V-III region WEA IGKV3D-20 Ig heavy chain V-III region TRO Ig kappa chain V-I region DEE Ig heavy chain V-III region WEA TRPC1Ig kappa chain V-II region RPMI 6410 Ig heavy chain V-II region OU Ig heavy chain V-II region ARH-77 AHCYL1 Ig heavy chain V-III region WEA Ig kappa chain V-II region RPMI 6410 Ig lambda chain V-III region SH Ig heavy chain V-III region KOL IGKV1-5(23-?) Ig lambda chain V region 4A IGHM REL CD19:VAV1Antigen Ig kappa chain V-I region Wes p-S559,S644,S652-CARD11 RELA PIK3R1 Ig kappa chain V-I region AU SHC1-2 Ca2+Ig kappa chain V-III region POM IGLC1 Ig lambda chain V-III region LOI GRB2-1 Ig kappa chain V-I region DEE Ig lambda chain V-I region NEW Ig lambda chain V-IV region Hil SH3KBP1 STIM1 IGLC1 Ig lambda chain V-I region NEWM Ig heavy chain V-I region HG3 PPIA Ig heavy chain V-II region NEWM PSMA6 IKBKG RASGRP1 Ig kappa chain V-I region Daudi Ig kappa chain V-I region AU Ig lambda chain V-IV region Kern DAG IKBKB ADPATPIGLC6 VAV1 Ig heavy chain V-III region BRO NF-kappaBp50,p65,c-Rel:ub-p-IKBPSMB5 IGKV2D-30 PhosphorylatedNFATC1,2,3Ig heavy chain V-III region JON Ig heavy chain V-III region BRO PSMD5 Ig kappa chain V-I region Gal IGKC Ig kappa chain V-I region Wes STIM1 CBL RELA IGKV1-5(23-?) ITPR2 PSMF1 Fe3+ Ig heavy chain V-II region WAH IGKV1-12 IGKC p-Y188,Y199-CD79A p-14S-NFATC2 Ig kappa chain V-I region Wes Ig kappa chain V-III region B6 Ig lambda chain V-IV region Bau IGHD MAP3K7 Ig heavy chain V-III region TRO IGLV(23-?) IGKV2D-30 IGLC7 p-CARMA1:MALT1:p-BCL10PIP3 activates AKTsignalingUb-21,22-p-S32,S36-NFKBIA PIK3AP1Ig heavy chain V-III region DOB PIK3R1 AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerNF-kappaBp50,p65,c-Rel dimerCalcineurin (CaN)PSMD3 PSMC4 Ig kappa chain V-I region AG Ig lambda chain V-II region BOH Ig heavy chain V-II region MCE Ig kappa chain V-III region POM Ig lambda chain V-I region VOR Ig heavy chain V-III region JON IGHV1-2 Ig heavy chain V-II region ARH-77 Ig heavy chain V-III region BRO FBXW11 Ig heavy chain V-III region TRO Ig kappa chain V-I region BAN IGLC6 Ig kappa chain V-I region HK101 Ig heavy chain V-II region ARH-77 IGLV(23-?) Ig lambda chain V-I region VOR IGLV(23-?) IGLC1 Ig kappa chain V region EV15 IGHV1-2 ADPIg lambda chain V-II region NEI Ig lambda chain V region 4A Ig lambda chain V-I region NEWM Ig lambda chain V-III region SH p-T133-RASGRP3 ITPR2 IGKV4-1(21-?) NAD+ Ig heavy chain V-III region CAM PTPN6 IGKV3D-20 Ig kappa chain V-I region Wes Ig kappa chain V-II region Cum Ig kappa chain V-I region HK101 IGKC IGHV(1-?) IGKV2D-30 Ig heavy chain V-III region KOL IGLV(23-?) Ig lambda chain V-II region MGC p-12S-NFATC1 IGHV1-2 Ig lambda chain V-IV region Hil CD22:Antigen:p-BCRIGHM IGKV2-28 NFKB1(1-433) Ig kappa chain V-I region Wes Ig kappa chain V-II region Cum Ig kappa chain V-I region AU p-6Y-SYK CUL1 PSMD9 IGLC3 Ig kappa chain V-II region Cum p-BCL10 CD19 Ig lambda chain V-I region VOR Ig heavy chain V-III region CAM UBC(381-456) p-6Y-SYK p-Y196,Y207-CD79B IGHV7-81(1-?) Ig heavy chain V-II region WAH Ig kappa chain V-I region AG IGKV3D-20 Ig heavy chain V-III region WEA SYKIg kappa chain V-I region Gal Ig lambda chain V-IV region Bau Ig kappa chain V-I region HK101 Ig kappa chain V region EV15 IGLC6 IGLC2 STIM1 p-S559,S644,S652-CARD11 Ig kappa chain V-II region FR Ig heavy chain V-III region TRO CD79A CD79A IGKC Ig lambda chain V-II region BOH ATPCALM1 Ig heavy chain V-II region NEWM ADPUBB(77-152) Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1Ig lambda chain V-IV region Kern IGLC2 Ig kappa chain V-I region Wes IGKVA18(21-?) PPP3R1 Ig kappa chain V-I region Gal Ig kappa chain V-II region Cum STIM1 DimerIg kappa chain V-I region HK101 I(1,4,5)P3 Ig heavy chain V-II region ARH-77 Ig lambda chain V-IV region Hil Ig lambda chain V region 4A Ig lambda chain V-II region TOG IGKVA18(21-?) IGLC6 Calcineurin:Phosphorylated NFATC1,2,3PSMA7 ORAI2 IGLC6 Ig lambda chain V-II region BOH Ca2+ p-Y188,Y199-CD79A VAV1 CUL1 Ig kappa chain V-III region B6 BTRC p-Y196,Y207-CD79B Ig lambda chain V-I region NEWM Ig kappa chain V-I region Gal Ig lambda chain V-I region HA Ig heavy chain V-III region JON IgH heavy chain V-III region VH26 precursor BTKIg heavy chain V-III region BUT Ig kappa chain V-III region VG Ig kappa chain V region EV15 Ig heavy chain V-II region MCE Ig kappa chain V-I region Daudi Ig heavy chain V-III region TRO Ig kappa chain V-II region RPMI 6410 SYK Ig lambda chain V-II region MGC Ig kappa chain V-II region RPMI 6410 Ig kappa chain V-I region Daudi Ig heavy chain V-III region DOB Ig kappa chain V-II region RPMI 6410 PI(3,4,5)P3DAPP1Ig kappa chain V-I region AU IGHV1-2 p-Y762,807,822-CD22 p-S19,S23-NFKBIB Ig kappa chain V-I region Daudi Ig heavy chain V-II region MCE IGKV2D-30 NCK1Ig heavy chain V-I region HG3 BTRC IGKV1-12 IGLC1 Ig kappa chain V-I region Gal IGKV1-12 Ig kappa chain V-III region B6 Antigen Ig lambda chain V-IV region Bau Ig lambda chain V region 4A PSMB6 p-S559,S644,S652-CARD11 Ig heavy chain V-II region OU Ig heavy chain V-I region HG3 PSME3 Ig lambda chain V-II region NEI IGHM IGHD Ig heavy chain V-II region NEWM p-Y762,807,822-CD22 ATPIGKV4-1(21-?) NRAS IGLC1 Ig kappa chain V-I region Gal NF-kappa-Bp50,p65,c-Rel:p-IKBIg lambda chain V-II region MGC Ig kappa chain V-I region DEE Ig lambda chain V-III region LOI Ig kappa chain V-II region FR SOS1 p-12S-NFATC1 Ig heavy chain V-I region HG3 Antigen:p-BCR:p-SYKIGHV7-81(1-?) Ig heavy chain V-III region BUT Ig lambda chain V-II region NEI Ig lambda chain V-I region VOR Ig heavy chain V-III region CAM Ig lambda chain V region 4A IGKV3D-20 Ig kappa chain V-I region Wes IGKV4-1(21-?) DephosphorylatedNFATC1,2,3Ca2+ IGKV2-28 IGHV(1-?) p-BCL10 Ig lambda chain V-I region NEW Ig lambda chain V-III region LOI Ig kappa chain V-II region Cum CBLB IGLC2 Ig lambda chain V-IV region Hil IGHV(1-?) Ig lambda chain V-VI region AR IGHV7-81(1-?) IGLC3 Ig lambda chain V-I region NEW IGKV4-1(21-?) p-S243-NFATC2 Ig kappa chain V-I region Wes IGKV3D-20 p-Y196,Y207-CD79B Antigen Ig heavy chain V-III region DOB IGHV1-2 SKP1 Ig kappa chain V-I region AG PLC gamma1,2PSMD14 Ig heavy chain V-III region KOL ADPZn2+ Ig lambda chain V-IV region Bau UbIg heavy chain V-III region JON Ig lambda chain V region 4A IgH heavy chain V-III region VH26 precursor p-T184-RASGRP1 Ig kappa chain V-III region POM IGHV1-2 Ig heavy chain V-I region EU RELA Ig heavy chain V-I region EU FBXW11 RELA Ig heavy chain V-III region BRO Ig lambda chain V-I region HA PSMD1 Ig lambda chain V-VI region AR Ig lambda chain V-III region SH IGLC7 p-Y188,Y199-CD79A PI(4,5)P2Ig kappa chain V-II region FR p-RASGRP1,3:DAGPRKCB CyclophilinA:Cyclosporin APSMA2 Ig lambda chain V-I region HA Ig kappa chain V-II region RPMI 6410 Ig kappa chain V-I region Gal Ig heavy chain V-III region BRO Ig lambda chain V-III region SH Ig lambda chain V-IV region Kern Ca2+ Ig heavy chain V-III region JON Ig kappa chain V-II region RPMI 6410 Ig heavy chain V-III region CAM IGKV1-5(23-?) IKBKB IGHD Ig lambda chain V-IV region Bau Ig kappa chain V-I region HK101 PSMA1 Ig kappa chain V-I region AU Ig heavy chain V-I region HG3 IGLC7 IGHV7-81(1-?) Ig kappa chain V-III region POM Ig lambda chain V-II region TOG KRAS Ig lambda chain V-II region BOH IGKV2-28 NFKB1(1-433) IGKV4-1(21-?) PSMD10 PLCG2 (BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)Ig kappa chain V region EV15 Ig heavy chain V-II region OU Ig heavy chain V-III region WEA IGLC1 IGKV1-12 IGHV(1-?) Ig lambda chain V-I region VOR NF-kappaBp50,p65,c-Rel dimerUBB(1-76) IGLV(23-?) BCRPTPN6UBC(533-608) Ig heavy chain V-II region OU Ig lambda chain V-IV region Hil Ig kappa chain V region EV15 IGLC2 IGLC3 IGKV4-1(21-?) IGKVA18(21-?) Ig lambda chain V-IV region Bau IGLC6 IGHD IGLC7 Ig lambda chain V-I region NEWM IGHV7-81(1-?) IGLC3 Ig lambda chain V-II region MGC STIM1 IKBKG Ig lambda chain V-II region BOH CBLB Ig heavy chain V-I region EU NF-kappa-Bp50,p65,c-Rel:IKBIg lambda chain V-IV region Bau Ig lambda chain V-II region TOG IGLC3 CD22Ig lambda chain V-II region BOH ATPIg lambda chain V-IV region Hil REL Ig kappa chain V-II region RPMI 6410 Ig lambda chain V-III region LOI Ig kappa chain V-III region POM PSMD4 Ig heavy chain V-II region OU Ig heavy chain V-II region MCE Ig heavy chain V-III region BUT Ig kappa chain V-I region HK101 IGHV(1-?) Ig lambda chain V-I region NEWM Ig heavy chain V-III region BUT PSMB2 Ig heavy chain V-II region NEWM IGKV1-12 ITPR3 Ig kappa chain V-I region AG Ig lambda chain V-II region TOG p-Y188,Y199-CD79A PI(4,5)P2IgH heavy chain V-III region VH26 precursor IGKC IGLV(23-?) Ig lambda chain V-II region BOH LYN,FYN,BLKIg lambda chain V-II region NEI ORAI dimerNAc-CD22homo-oligomerRELA Ig lambda chain V-I region NEW Ig kappa chain V-II region FR UBC(1-76) IGHM 26S proteasomeIGLC7 GRB2-1 Ig heavy chain V-II region ARH-77 Ig kappa chain V-I region Daudi Ig lambda chain V-II region NEI Ig kappa chain V region EV15 ATPIg kappa chain V-II region RPMI 6410 PIK3R1 Ig lambda chain V-IV region Hil IGLC7 p-CARMA1 OligomerNF-kappaB:p-IkB:SCF-betaTrCPIg kappa chain V-II region Cum Ig lambda chain V-II region NEI Ig heavy chain V-III region BRO Ig heavy chain V-III region WEA Ig heavy chain V-III region JON ITPR:I(1,4,5)P3tetramerIGLC1 IGKC Antigen:p-BCRIg lambda chain V-I region NEW Ig heavy chain V-I region EU Ig heavy chain V-III region DOB p-S177,S181-IKBKB Ig heavy chain V-II region WAH Ig heavy chain V-III region BRO p-S19,S23-Ub-NFKBIB IGLV(23-?) GDP Ig heavy chain V-III region KOL IGKV1-5(23-?) IGLC6 NFKB1(1-433) p-S559,S644,S652-CARD11 HRAS Ig heavy chain V-III region TRO Ig heavy chain V-III region CAM IGLC1 Ig lambda chain V-II region BOH Ig heavy chain V-I region HG3 UBC(305-380) IGHD PSMB10 p-5Y-BLNK VAV1 Ig lambda chain V-II region MGC TRPC1 Antigen Ig heavy chain V-II region WAH IGKV1-12 IGHV(1-?) STIM1:CalciumIGHD Ig kappa chain V-II region FR Ig heavy chain V-III region TRO Ig lambda chain V-I region HA IGKV2D-30 IGKV2-28 NCK1 PSME1 IGKVA18(21-?) Ig kappa chain V-I region AG Ig lambda chain V-II region TOG CRAC channelIg kappa chain V-I region HK101 ITPR1 MALT1 IGKV4-1(21-?) Ig kappa chain V-II region RPMI 6410 PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRIg heavy chain V-III region CAM Ig kappa chain V-I region AU Ig heavy chain V-II region ARH-77 Ig heavy chain V-I region HG3 IGHD Ig heavy chain V-III region TRO p-13S-NFATC3 IGHD VAV1Ig heavy chain V-II region WAH ATPIg lambda chain V-I region HA IGHV1-2 IGKV1-5(23-?) Ig lambda chain V-IV region Bau IGLC7 RASGRP3 p-Y762,807,822-CD22:Antigen:p-BCRIg heavy chain V-II region MCE Ig kappa chain V-II region Cum IGKV2-28 Ig heavy chain V-II region ARH-77 IGKV2-28 IGLC3 Ig kappa chain V-II region Cum BLNK (SLP-65)Signalosomep-S157,S161-NFKBIE STIM1:TRPC1Ig lambda chain V-I region HA Ig kappa chain V-III region POM Ig lambda chain V-IV region Kern UBC(457-532) Ig kappa chain V-I region Daudi PSMB1 Ig heavy chain V-II region OU Ig lambda chain V-II region TOG Ig lambda chain V-IV region Kern MALT1 Ig kappa chain V-I region Wes Ig lambda chain V-VI region AR DAGPSMB3 Ig lambda chain V-I region HA IGHV(1-?) Ig heavy chain V-II region NEWM Ig lambda chain V-IV region Kern Ig kappa chain V region EV15 p-Y194,Y195,Y272-SHC1-3 SOS1 PLCG1 Ig lambda chain V-IV region Kern Ig lambda chain V-II region NEI IgH heavy chain V-III region VH26 precursor IGHM Ig kappa chain V-II region FR Ig lambda chain V-II region MGC p-S257-NFATC1 Ig lambda chain V-I region NEW IGKV1-12 HRAS Ig kappa chain V-II region FR Ig heavy chain V-II region MCE Ig lambda chain V-I region NEWM IGKV1-12 Ig heavy chain V-II region WAH Fe3+ PSMC2 p-Y753,Y759,Y1217-PLCG2 Ig heavy chain V-III region TRO BLNK IGLC3 Ig lambda chain V-I region VOR IGKV3D-20 ITPR3 Ig heavy chain V-III region CAM GRB2-1PSMA4 Ig lambda chain V-VI region AR IGLC2 Ig kappa chain V region EV15 CBLB PPP3R1 Antigen Ig heavy chain V-II region WAH Ig kappa chain V-II region Cum p-Y188,Y199-CD79A IGKV2-28 Ig heavy chain V-III region KOL IGHV7-81(1-?) p-Y196,Y207-CD79B Ig kappa chain V-I region Daudi Ig lambda chain V-I region VOR PIK3CD MyrG2-PalmC3-LYN BLNK:GRB2:SOS1:CIN85:CBLIg heavy chain V-II region ARH-77 Ig heavy chain V-II region OU Ig heavy chain V-III region KOL REL FKBP1A:TacrolimusIg heavy chain V-III region WEA p-5Y-BLNK UBC(153-228) Zn2+ Ig kappa chain V region EV15 Ig heavy chain V-II region WAH MyrG2-PalmC3,6-FYN IGKV4-1(21-?) Ig lambda chain V-IV region Kern Ig heavy chain V-III region KOL Ig lambda chain V-I region NEW IGHV7-81(1-?) IGHM RASGRP1,3p-Y771,Y783-PLCG1 Ig lambda chain V-I region VOR Ig lambda chain V-III region SH IKBKG Ig kappa chain V-III region POM Antigen Ig lambda chain V-VI region AR IgH heavy chain V-III region VH26 precursor IGLC1 IGHD Ig lambda chain V-I region NEWM CD19 SignalosomeREL CBL Ig lambda chain V-I region VOR CARD11 p-S32,S36-NFKBIA ATPPIK3CD p-Y196,Y207-CD79B RELA IGLC7 PIK3CD:PIK3R1Ig lambda chain V-I region VOR IGKC Ca2+IGHM Ig lambda chain V-IV region Bau Ig kappa chain V-II region Cum ITPR2 Ca2+ MALT1 REL UBC(77-152) IGKV1-5(23-?) IGKV1-5(23-?) Ig lambda chain V-III region SH Ig kappa chain V-I region BAN MyrG2-BLK p-Y139-DAPP1 NFKBIE IGHM BCAP SignalosomeIg lambda chain V-III region SH Ig heavy chain V-III region DOB UBC(609-684) Ig kappa chain V-III region VG PSMD11 Ig kappa chain V-I region AU Ig kappa chain V-III region VG IGKV2D-30 Ig kappa chain V-I region AG IGKV2D-30 IGKC IGKVA18(21-?) Ig kappa chain V-I region DEE PSMD12 PSMC1 Ig lambda chain V region 4A p-S32,S36-NFKBIA Ig heavy chain V-I region EU Ig kappa chain V-I region BAN NFKB1(1-433) IGLC6 p-6Y-CD19 PSMA8 Ig heavy chain V-II region NEWM IGHM UBA52(1-76) CHUK:IKBKB:IKBKGIg lambda chain V-VI region AR p-BCL10 ORAI2 PIK3CD Ig heavy chain V-I region HG3 Ig lambda chain V-II region MGC IGKV2-28 Ig kappa chain V-I region BAN p-Y239,Y240,Y317-SHC1-2 Ig kappa chain V-III region B6 Ig lambda chain V-III region LOI IGKV3D-20 Ig heavy chain V-III region CAM Ig lambda chain V-II region TOG p21 RAS:GDPIGHV7-81(1-?) IGLC6 p-6Y-SYK Ig kappa chain V-III region VG Ig kappa chain V-I region DEE Ig kappa chain V-I region Gal IGKV2-28 PI(4,5)P2IGLC3 Ig heavy chain V-III region JON NFKB1(1-433) IGKV2D-30 Ig kappa chain V-I region AU Ig lambda chain V-II region TOG PIK3R1 IgH heavy chain V-III region VH26 precursor Ig kappa chain V-II region FR Ig kappa chain V-III region VG Ig heavy chain V-III region BRO Ig heavy chain V-II region NEWM Ig kappa chain V-I region HK101 Ig kappa chain V-III region VG PSMC5 Ig kappa chain V-I region Daudi Ig heavy chain V-III region WEA Ig lambda chain V-I region NEWM IGLC2 IGHM IGLV(23-?) Ig lambda chain V-I region NEWM Ig kappa chain V-I region DEE Antigen:BCRIg heavy chain V-III region BUT IGLC2 Ig kappa chain V-III region B6 Active IKK complexIg heavy chain V-III region JON IGLC1 CBL IGHV(1-?) Ig kappa chain V-I region AG Ig lambda chain V-IV region Hil Ig heavy chain V-III region DOB CD79B Ig kappa chain V region EV15 p-CARMA1:MALT1:p-BCL10:TAK1:IKKIg heavy chain V-III region DOB Ig kappa chain V-I region AG IGLC7 Ig heavy chain V-III region WEA Ig heavy chain V-III region BUT PIK3CD:PIK3R1IGKV4-1(21-?) Ig heavy chain V-II region MCE Ig kappa chain V-III region POM IGKV1-5(23-?) SHC1-3 Ig kappa chain V-I region Wes IGKVA18(21-?) NAc-CD22Ig lambda chain V region 4A PSMA3 Ig lambda chain V-I region HA IGLV(23-?) PSME4 Ig kappa chain V-I region BAN CALM1 PSMB8 Ig heavy chain V-II region NEWM Ig lambda chain V-II region NEI I(1,4,5)P3 PSMB11 IGKVA18(21-?) Ig kappa chain V-III region VG NFKB1(1-433) SH3KBP1 PSMC3 IGKV3D-20 Ig heavy chain V-I region HG3 Ig lambda chain V-III region LOI Ig kappa chain V-III region VG Ig lambda chain V-VI region AR Ig heavy chain V-III region BUT IgH heavy chain V-III region VH26 precursor Antigen Ig heavy chain V-II region OU Ig heavy chain V-II region NEWM Antigen Ig kappa chain V-I region Gal IgH heavy chain V-III region VH26 precursor I(1,4,5)P3p-S19,S23-NFKBIB GRB2-1 IGKVA18(21-?) Ig heavy chain V-II region OU NRAS Ig heavy chain V-III region WEA RPS27A(1-76) Ig lambda chain V-II region NEI SKP1 PI(3,4,5)P3 IGHV(1-?) p-14S-NFATC2 Ig lambda chain V-III region LOI Ig heavy chain V-III region DOB Ig kappa chain V-I region HK101 Ig heavy chain V-III region DOB Ig lambda chain V-III region SH NFKBIA CALM1IGKV3D-20 CHUK Ig lambda chain V-IV region Hil MAP3K7Ig heavy chain V-III region BRO Ig lambda chain V-III region SH SOS1 IGHV1-2 Ig lambda chain V-IV region Hil Ig kappa chain V-III region POM CALM1:4xCa2+NFKBIB Ig lambda chain V-II region MGC ITPR3 IGHV1-2 IGKV3D-20 Ig lambda chain V-I region HA p-BCL10p-Y196,Y207-CD79B ORAI1 IGLC2 IGKV1-12 Ig heavy chain V-III region BUT Ig lambda chain V-II region MGC Ig lambda chain V-IV region Kern Ig kappa chain V-III region B6 Ig kappa chain V-III region B6 Ig heavy chain V-III region CAM PPP3CB IGHV7-81(1-?) Ig lambda chain V-I region HA p-S265-NFATC3 Ig heavy chain V-III region KOL KRAS Ig heavy chain V-I region EU IGKC Ig kappa chain V-III region B6 CHUK IGKV2D-30 PSIGKV2-28 ITPR1 Ig kappa chain V-I region AG GRB2-1 Ig lambda chain V-II region TOG Ig lambda chain V-III region SH Ig kappa chain V-I region Daudi CD79B IGKVA18(21-?) Ig heavy chain V-I region EU Ig lambda chain V region 4A Ig heavy chain V-III region TRO SHFM1 Ig kappa chain V-I region BAN Ig kappa chain V-II region FR Ig lambda chain V-III region LOI PPP3CA IGKVA18(21-?) IGKV4-1(21-?) IGLC2 Ig heavy chain V-III region KOL ADPp-S157,S161-Ub-NFKBIE FKBP1A CARMA1 oligomerIg kappa chain V-II region FR p-S157,S161-NFKBIE MyrG2-PalmC3-LYNIg kappa chain V-I region BAN Ig heavy chain V-III region DOB Ig heavy chain V-II region OU Ig heavy chain V-II region NEWM PSMD2 p-Y223,Y551-BTK p-13S-NFATC3 Ig heavy chain V-II region MCE Ig kappa chain V-I region DEE UBB(153-228) UBC(229-304) ADPIg heavy chain V-II region ARH-77 Ig kappa chain V-I region BAN PSMC6 Ig lambda chain V region 4A IGLC3 PSMB7 PSMB4 Ca2+PSMD6 p-Y196,Y207-CD79B CHUK IGKV1-5(23-?) IP3 receptorhomotetramerIg heavy chain V-I region EU Ig lambda chain V-I region NEW p-CARMA1:MALT1:p-BCL10:TAK1PIK3CD Ig lambda chain V-I region NEW Ig heavy chain V-II region MCE IGLC6 Ig lambda chain V-III region LOI PSMD8 IGLC2 ADPIg kappa chain V-I region AU PSMD13 SHC1-2,SHC1-3Ig kappa chain V-I region Daudi ADPIg kappa chain V-I region AU Ig lambda chain V-VI region AR Ig lambda chain V-IV region Kern p-Y188,Y199-CD79A 26, 3676105138, 131, 15514179, 80, 146, 16890, 1635030, 50, 70, 110, 113371204163, 713353, 97, 16961, 9349, 95, 105, 13330, 70, 113, 12524, 41714497, 1695015911920111131


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: 65
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  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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CompareRevisionActionTimeUserComment
112687view16:08, 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

View all...
NameTypeDatabase referenceComment
(BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)ComplexR-HSA-1168601 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
ATPMetaboliteCHEBI:15422 (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: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:CIN85:CBLComplexR-HSA-983692 (Reactome)
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)
CBL ProteinP22681 (Uniprot-TrEMBL)
CBLB ProteinQ13191 (Uniprot-TrEMBL)
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)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
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 ProteinP0CG05 (Uniprot-TrEMBL)
IGLC3 ProteinP0CG06 (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)
KRAS ProteinP01116 (Uniprot-TrEMBL)
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:15846 (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)
NRAS ProteinP01111 (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)
PIK3AP1ProteinQ6ZUJ8 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3CD:PIK3R1ComplexR-HSA-1045152 (Reactome)
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.
PLC gamma1,2ComplexR-HSA-1169089 (Reactome)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG2 ProteinP16885 (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)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
SHC1-2,SHC1-3ComplexR-HSA-1169480 (Reactome) SHC1 isoforms p46 and p52 are found in B cells (Smit et al. 1994).
SHC1-3 ProteinP29353-3 (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-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-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-Y188,Y199-CD79A ProteinP11912 (Uniprot-TrEMBL)
p-Y194,Y195,Y272-SHC1-3 ProteinP29353-3 (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-Y239,Y240,Y317-SHC1-2 ProteinP29353-2 (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)
p-Y771,Y783-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
(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-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-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:SOS1ArrowR-HSA-983703 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1R-HSA-983704 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNK:CIN85:GRB2:SOS1mim-catalysisR-HSA-983704 (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-983704 (Reactome)
BCAP Signalosomemim-catalysisR-HSA-2045911 (Reactome)
BCRR-HSA-983696 (Reactome)
BLNK (SLP-65) SignalosomeArrowR-HSA-983704 (Reactome)
BLNK (SLP-65) Signalosomemim-catalysisR-HSA-1112666 (Reactome)
BLNK:GRB2:SOS1:CIN85:CBLR-HSA-983703 (Reactome)
BTKR-HSA-983704 (Reactome)
BTKmim-catalysisR-HSA-983704 (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-983704 (Reactome)
CD19 Signalosomemim-catalysisR-HSA-2076220 (Reactome)
CD19:VAV1R-HSA-983704 (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-983704 (Reactome)
Dephosphorylated NFATC1,2,3ArrowR-HSA-2025882 (Reactome)
FKBP1A:TacrolimusTBarR-HSA-2025882 (Reactome)
GRB2-1R-HSA-983704 (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,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-983704 (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(4,5)P2R-HSA-1112666 (Reactome)
PI(4,5)P2R-HSA-2045911 (Reactome)
PI(4,5)P2R-HSA-2076220 (Reactome)
PI(4,5)P2R-HSA-983704 (Reactome)
PIK3AP1R-HSA-983704 (Reactome)
PIK3CD:PIK3R1R-HSA-983704 (Reactome)
PIK3CD:PIK3R1mim-catalysisR-HSA-983704 (Reactome)
PLC gamma1,2R-HSA-983704 (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.
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-983704 (Reactome) Phosphorylated SYK phosphorylates BLNK (SLP-65, Fu et al. 1998, Chiu et al. 2002) and BCAP (inferred from mouse, Okada et al. 2000). Effector molecules are then recruited: 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.
As inferred from chicken DT40 cells and mouse B cells (Okada et al. 2000), phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates Phospholipase C gamma-2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004).
Phosphorylated BLNK recruits PLC gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).
SYK phosphorylates SHC which then binds GRB2 (Saxton et al. 1994, Harmer and DeFranco 1997).
CD19 in a stable complex with VAV1 is phosphorylated by Src kinases (inferred from mouse, Xu et al. 2002) and possibly by LYN (inferred from mouse, Fujimoto et al. 2000) in response to BCR activation. Phosphorylated CD19 then 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, which competes with VAV1 for the same binding site on CD19 (Brooks et al. 2000, Brooks et al. 2004).
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)
SHC1-2,SHC1-3R-HSA-983704 (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-983704 (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-RASGRP1,3:DAGArrowR-HSA-1168374 (Reactome)
p-RASGRP1,3:DAGmim-catalysisR-HSA-1168636 (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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