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

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1, 3, 5, 6, 17...68, 70, 89, 95, 9714, 21, 39, 42, 45...2, 58, 102, 1605, 24, 49, 61, 113...31, 35, 48, 78, 137...36, 82, 1506, 28, 34, 60, 73...54, 70, 108, 110, 12138, 106, 124, 12811, 53, 80, 112, 117...4, 25, 40, 94, 133...9, 15, 39, 52, 107...8, 100, 149, 15431, 35, 48, 78, 137...3, 56, 61, 65, 74...22, 37, 57, 83, 1459110, 19, 63, 15343, 69, 14712, 20, 36, 82, 15093, 114, 130, 138, 15829, 30, 125, 135, 14176, 98, 1633232, 130, 1387, 50, 67, 71, 88...28, 116, 129, 1552, 51, 58, 84, 99...64, 76, 98, 16332, 114, 12046, 72, 111endoplasmic reticulum lumencytosolplasma membranenucleoplasmIg lambda chain V-IV region Kern IGKV2-28 ADPIg heavy chain V-II region NEWM STIM1:TRPC1IGKC TRPC1Ig kappa chain V-I region Gal SRMS PSMA4 Ig kappa chain V-I region HK101 IGKV3D-20 Ig kappa chain V region EV15 Ig heavy chain V-III region TRO p-Y188,Y199-CD79A Ig heavy chain V-II region OU PSMD7 PSMA3 Ig kappa chain V-I region HK101 p-Y139-DAPP1 Ig heavy chain V-I region EU NF-kappaB:p-IkB:SCF-betaTrCPITPR2 CD22 Ca2+PPP3CB Ig lambda chain V region 4A ORAI1 PSMD4 IGKV3D-20 RELA PIK3CD:PIK3R1Ig heavy chain V-II region ARH-77 Ig kappa chain V-II region Cum Ig kappa chain V-II region Cum Ig lambda chain V-IV region Hil Ig heavy chain V-III region BUT Ig kappa chain V-I region Wes IgH heavy chain V-III region VH26 precursor IGLC2 Ig kappa chain V-II region Cum CBLB Ig heavy chain V-III region JON VAV1 PSMB4 IGHV7-81(1-?) Ig kappa chain V-I region Wes I(1,4,5)P3 MAP3K7 IGKV4-1(21-?) Ig kappa chain V-II region FR CD19 Signalosomep-Y223,Y551-BTK FYNPSMC4 Ig kappa chain V-I region HK101 p-Y771,Y783-PLCG1 Ig kappa chain V-I region Gal IGLC2 IGHV7-81(1-?) CARMA1 oligomerIg heavy chain V-II region MCE IGKV2D-30 Ig lambda chain V-VI region AR Ig heavy chain V-I region EU IGKV2-28 IGHM Ig kappa chain V-III region B6 LYNIg kappa chain V-III region POM Ig kappa chain V-II region FR Ig lambda chain V-III region LOI ATPIg heavy chain V-I region EU NFKB1(1-433) Ig kappa chain V-I region Daudi IGLV(23-?) IGLC1 Ig heavy chain V-II region OU Ig lambda chain V-II region NEI IGKVA18(21-?) Antigen ATPIg kappa chain V-II region FR IGLC7 Ig kappa chain V-I region Wes RELA Ig lambda chain V-I region NEW SOS1 Ig kappa chain V-III region VG PSMB11 NFKB1(1-433) Ig heavy chain V-II region OU Ig heavy chain V-II region WAH Ig heavy chain V-I region HG3 IGKVA18(21-?) PSMA8 p-S19,S23-Ub-NFKBIB Calcineurin:Phosphorylated NFATC1,2,3Ig heavy chain V-III region CAM Ig kappa chain V-I region HK101 REL Ig kappa chain V-III region B6 IgH heavy chain V-III region VH26 precursor IGKVA18(21-?) Ig heavy chain V-II region OU Ig lambda chain V-IV region Bau IGHV7-81(1-?) IGKVA18(21-?) Ig heavy chain V-II region WAH CD79A FBXW11 Ig kappa chain V-I region HK101 IGKVA18(21-?) Ig kappa chain V-I region Daudi Ig lambda chain V-III region LOI Ig heavy chain V-II region NEWM Ig lambda chain V-IV region Bau Ig heavy chain V-III region TRO FKBP1A Ig kappa chain V-III region VG Ig kappa chain V-I region DEE IGHV1-2 PPP3CA IGKV4-1(21-?) IGLC1 PPIA Ig heavy chain V-III region KOL Ig heavy chain V-II region NEWM CUL1 UBC(305-380) Ig heavy chain V-III region KOL IKBKG Ig lambda chain V-I region HA VAV1Ig heavy chain V-II region ARH-77 Ig heavy chain V-II region OU Ig lambda chain V-II region NEI Ig heavy chain V-III region DOB IGKV1-5(23-?) p-6Y-SYK SHC1-2 IGKC Ig lambda chain V-III region SH Ig heavy chain V-II region WAH IGKV2-28 p-CARMA1:MALT1:p-BCL10:TAK1Ig lambda chain V-II region TOG Ig lambda chain V-II region NEI Ig kappa chain V-II region Cum BTRC Ig heavy chain V-II region WAH Ig kappa chain V-I region AU Ig lambda chain V-VI region AR Ig lambda chain V-I region HA Ig kappa chain V-II region FR UbIg kappa chain V-I region AG IGLC6 p-Y196,Y207-CD79B Ig kappa chain V-I region AU p-S559,S644,S652-CARD11 Ig lambda chain V-I region NEWM NFKB1(1-433) CRAC channelPLCG2 ORAI dimerIg heavy chain V-III region BUT ADPIg heavy chain V-III region WEA Ig heavy chain V-II region ARH-77 Ig heavy chain V-III region TRO UBC(77-152) CD22IGKV1-5(23-?) Ig lambda chain V-I region HA CALM1 IGHV1-2 Ig lambda chain V-II region NEI PSMB6 Ca2+IGHD Ig lambda chain V-II region MGC NF-kappa-Bp50,p65,c-Rel:IKBPSMD9 Ig heavy chain V-II region NEWM Ig lambda chain V region 4A Ig kappa chain V-I region AU IGHV1-2 TRPC1 PI(4,5)P2Antigen Ig heavy chain V-III region CAM Antigen p-5Y-BLNK Ig heavy chain V-III region JON Ig lambda chain V-III region LOI CBLB Ig kappa chain V-III region POM Ig heavy chain V-I region EU Ig heavy chain V-III region KOL SOS1 p-BCL10KRAS Ig heavy chain V-III region WEA ADPIGKV2-28 Ig lambda chain V-II region BOH CHUK PSMA7 Ig heavy chain V-III region BUT ADPMALT1 BLNK:GRB2:SOS1:CIN85:CBLIg lambda chain V-III region SH IGHV(1-?) Ig lambda chain V-I region VOR IGKV1-12 IGHM IGLC2 CUL1 IGLC2 CHUK:IKBKB:IKBKGPSMC1 Ig heavy chain V-II region WAH REL Ig lambda chain V-II region MGC Ig lambda chain V-IV region Kern IGKV1-5(23-?) Ig lambda chain V-I region NEWM Ig heavy chain V-III region BUT PhosphorylatedNFATC1,2,3IGKV2D-30 Ig kappa chain V-I region Gal ITPR2 Ig heavy chain V-III region TRO IGLV(23-?) Ig heavy chain V-III region DOB Ig lambda chain V region 4A Ig heavy chain V-III region JON Ig kappa chain V-II region FR Ig heavy chain V-III region WEA Ig kappa chain V-I region Daudi p-Y188,Y199-CD79A Ig lambda chain V-IV region Kern Ig heavy chain V-II region MCE Ig heavy chain V-III region TRO p-S157,S161-Ub-NFKBIE Ig lambda chain V-II region NEI NAc-CD22IGHM Ig kappa chain V-III region B6 Cyclosporin A IGHV7-81(1-?) Ig heavy chain V-II region OU IGKC Ig heavy chain V-III region BRO IGKVA18(21-?) Ig kappa chain V-II region FR p-BCL10 IGLC3 VAV1 Ig kappa chain V-I region BAN Ig lambda chain V-I region HA PRKCB Ig heavy chain V-III region JON p-CARMA1:MALT1:p-BCL10:TAK1:IKKp-6Y-CD19 Ig lambda chain V region 4A Ig lambda chain V-I region VOR Ig kappa chain V-I region BAN Ig kappa chain V-I region AG Ig kappa chain V-I region Wes DAPP1p-12S-NFATC1 ITPR1 Ig lambda chain V-VI region AR CBL Ig lambda chain V-II region BOH Ig lambda chain V-II region MGC ITPR1 IGKV4-1(21-?) DAG Ig heavy chain V-III region WEA ORAI2 IGHV(1-?) Ig heavy chain V-III region JON IgH heavy chain V-III region VH26 precursor PSMA5 Ig heavy chain V-III region CAM Ig lambda chain V-III region LOI p-Y762,807,822-CD22 Ig heavy chain V-III region BRO IGHV(1-?) IGKVA18(21-?) Ig kappa chain V-III region VG Ig heavy chain V-II region NEWM Ig lambda chain V-II region BOH Ig heavy chain V-III region BRO CD79B IKBKG Ig lambda chain V-II region MGC STIM1 IGKC Ig kappa chain V-II region RPMI 6410 IGLC2 REL Ca2+ Antigen:p-BCR:p-SYKGDP ITPR3 IGKVA18(21-?) Ig heavy chain V-I region EU ATPIg lambda chain V-I region NEWM SHFM1 IGKC IGKV2-28 Ig lambda chain V-II region NEI p-Y753,Y759,Y1217-PLCG2 Ig lambda chain V region 4A Ig kappa chain V-I region HK101 Ig kappa chain V-I region DEE PIK3CD Ig lambda chain V-III region SH Ig heavy chain V-II region OU MALT1 Ig heavy chain V-III region DOB Antigen Ig lambda chain V-III region LOI IGLC7 IGHM IGLC1 Ig lambda chain V-VI region AR Ig lambda chain V-IV region Hil Ig lambda chain V-III region SH IGKV4-1(21-?) Ig heavy chain V-III region KOL ITPR3 Ig lambda chain V-I region NEW IGKV1-12 PSME3 Ig lambda chain V-III region SH p-Y196,Y207-CD79B IGHM PSIg lambda chain V-VI region AR Ig lambda chain V-II region BOH Ig kappa chain V-II region FR p-S559,S644,S652-CARD11 Ig lambda chain V-I region HA Ig heavy chain V-II region ARH-77 PSMB10 REL Ig kappa chain V-III region VG Ig lambda chain V-IV region Kern IgH heavy chain V-III region VH26 precursor PIK3CD Ig lambda chain V-III region SH PSMB3 IGLC1 Antigen:p-BCRIg kappa chain V-II region RPMI 6410 Ig kappa chain V-II region FR NRAS Ig kappa chain V-III region B6 Ig kappa chain V-II region RPMI 6410 IGLC6 Ig kappa chain V-I region DEE IGKV2D-30 Ig heavy chain V-II region NEWM IGKV1-5(23-?) Ig heavy chain V-III region KOL RELA IP3 receptorhomotetramerPSMA6 Ig heavy chain V-I region EU Ig lambda chain V-IV region Kern Ig kappa chain V-III region B6 PPP3CB Ig kappa chain V-I region BAN PSMF1 BLK Ig lambda chain V-II region BOH BLNK (SLP-65)SignalosomeIg lambda chain V-II region TOG IGKV3D-20 IGLC1 Ig kappa chain V-II region Cum Ig kappa chain V region EV15 PSMB1 PIK3CD:PIK3R1PPP3CA p-Y188,Y199-CD79A CBL PSME1 ATPIg heavy chain V-III region BUT Ig heavy chain V-II region WAH IGLC2 PSMB7 Ig lambda chain V-II region NEI REL GRB2-1 Ig heavy chain V-III region WEA MAP3K7 IGLV(23-?) STIM1 Ig lambda chain V-II region NEI IGLC6 p-RASGRP1,3:DAGPI(3,4,5)P3 IgH heavy chain V-III region VH26 precursor p-S559,S644,S652-CARD11 ADPNCK1Ig heavy chain V-III region CAM Ig heavy chain V-III region BUT PPP3R1 ATPIg kappa chain V-II region Cum IGKC p-S157,S161-NFKBIE IGHV(1-?) Ig heavy chain V-II region OU Antigen Ig heavy chain V-III region TRO p-Y196,Y207-CD79B IGHV7-81(1-?) Ig kappa chain V-I region Gal Ig heavy chain V-II region NEWM Ig heavy chain V-II region OU Ig heavy chain V-III region JON PS IGLV(23-?) Ig heavy chain V-III region TRO GRB2-1 IgH heavy chain V-III region VH26 precursor IgH heavy chain V-III region VH26 precursor AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerp-S19,S23-NFKBIB Ig lambda chain V-II region MGC Ig lambda chain V-II region NEI Ig heavy chain V-I region HG3 p-S32,S36-NFKBIA Ig lambda chain V-II region MGC CALM1:4xCa2+CBL NFKB1(1-433) Ig heavy chain V-III region BUT Ig lambda chain V-IV region Hil PI(3,4,5)P3Ig lambda chain V-II region TOG Ig heavy chain V-II region ARH-77 UBB(153-228) Ig heavy chain V-III region JON p-Y196,Y207-CD79B IGHM IGKV2D-30 Ig heavy chain V-III region DOB Ig kappa chain V-I region AG IGHV7-81(1-?) GTP IGLC3 IGHV1-2 Ig kappa chain V-I region Daudi IGKV3D-20 IGKV2-28 Ig lambda chain V-II region MGC Ig kappa chain V-II region Cum NFKBIE p-Y196,Y207-CD79B p-5Y-BLNK IGKV3D-20 Ig heavy chain V-III region DOB ORAI2 Ig kappa chain V-II region FR Ig lambda chain V-VI region AR Ig lambda chain V-III region SH IGKC Ig lambda chain V-I region NEW ATPPIK3R1 p-Y762,807,822-CD22 SH3KBP1 Ig kappa chain V-III region B6 IGLV(23-?) IGKC NFKB1(1-433) Ig lambda chain V region 4A KRAS Ig kappa chain V-I region AU Ig heavy chain V-I region HG3 IGLC1 Ig lambda chain V-IV region Hil IGLC3 GRB2-1 Ig kappa chain V-I region HK101 FBXW11 Ig kappa chain V region EV15 Ig lambda chain V region 4A Ig lambda chain V-I region NEW REL PRKCBIg heavy chain V-I region HG3 UBC(457-532) p-S265-NFATC3 IGHD Ig heavy chain V-II region MCE Ig heavy chain V-III region BUT Ig heavy chain V-III region KOL IGHV7-81(1-?) Ig heavy chain V-III region CAM Ig kappa chain V-I region AU SH3KBP1 Ig kappa chain V-I region Daudi Ig heavy chain V-III region CAM IGKV1-12 IGLC6 Ig lambda chain V-IV region Hil Ig lambda chain V-I region HA Ig lambda chain V-I region HA ATPIg heavy chain V-III region TRO Ig lambda chain V-VI region AR NF-kappaBp50,p65,c-Rel:ub-p-IKBPSMC3 Ig heavy chain V-III region DOB Ig lambda chain V-II region TOG Ig lambda chain V-VI region AR IGLC2 IgH heavy chain V-III region VH26 precursor p-13S-NFATC3 IGKV1-12 IGKV3D-20 SYKBTKIGHV1-2 BCRp-S559,S644,S652-CARD11 Ig lambda chain V-I region HA Ig lambda chain V-III region LOI IGLC1 CyclophilinA:Cyclosporin APLCG1 Ig lambda chain V-IV region Kern Ig kappa chain V-III region B6 Ig lambda chain V-I region NEWM Ig lambda chain V-I region VOR IGHM CD79B Ig kappa chain V-I region Gal Ig kappa chain V-I region DEE PTPN6Ig heavy chain V-II region MCE p-Y194,Y195,Y272-SHC1-3 IGHV7-81(1-?) IGKV1-5(23-?) Ig kappa chain V-II region Cum Ig kappa chain V region EV15 RASGRP3 Ig heavy chain V-II region ARH-77 Ig kappa chain V-III region B6 GRB2-1AntigenIg heavy chain V-III region CAM IGHD Ig lambda chain V-I region VOR Ig kappa chain V region EV15 PSMB8 Ig lambda chain V-II region MGC p-Y196,Y207-CD79B PLC gamma1,2CD19 Ig heavy chain V-III region BRO p-6Y-SYK IGHV7-81(1-?) IGHM Ig lambda chain V-IV region Bau Ig kappa chain V-I region Daudi SH3KBP1 Ig kappa chain V-I region Gal Ig kappa chain V-III region VG ADPIGKV1-5(23-?) IGKV1-5(23-?) IGKV1-12 Ig lambda chain V-IV region Kern Ig heavy chain V-III region DOB Ig heavy chain V-II region ARH-77 IGHV1-2 Ig heavy chain V-II region NEWM Ig kappa chain V-III region POM Ig kappa chain V-I region Daudi IGKV1-5(23-?) Ig kappa chain V-I region DEE Ig kappa chain V-I region Gal Antigen:p-BCR:p-SYK:p-BLNKIGKV4-1(21-?) p-S243-NFATC2 Ig heavy chain V-II region MCE Ig kappa chain V-I region DEE p-14S-NFATC2 Ig lambda chain V-I region VOR Ig lambda chain V-IV region Kern Ig heavy chain V-III region BUT IGLC3 Active IKK complexIGHV(1-?) CD19:VAV1ITPR1 BLNK IGLV(23-?) PSMB9 Ig kappa chain V-I region DEE Ig kappa chain V-I region Daudi SOS1 Ig heavy chain V-II region MCE Ig lambda chain V-I region NEWM Ig lambda chain V-IV region Bau Ig kappa chain V-I region BAN Ig lambda chain V-II region MGC MAP3K7Ig kappa chain V-I region AU IGLC7 Ig lambda chain V-II region TOG IGKV3D-20 Calcineurin (CaN)IGHD IGKC PSMC5 CALM1 Ig kappa chain V-I region Wes SHC1-3 IKBKB Ig heavy chain V-III region BRO IGLV(23-?) RELA Ig lambda chain V-VI region AR Antigen IGKVA18(21-?) Ca2+Ig lambda chain V-II region TOG IKBKB p-BCL10 Ig lambda chain V-I region VOR GRB2-1 Ig lambda chain V-I region NEWM PSMA2 Ig lambda chain V-I region NEW Ig lambda chain V-III region SH Ig kappa chain V region EV15 ITPR:I(1,4,5)P3tetramerIGLC6 Antigen:p-BCR:SYKIGHV7-81(1-?) Ig heavy chain V-III region CAM PIK3AP1Ig lambda chain V-IV region Hil Fe3+ DAG Ig lambda chain V-II region BOH IGHD Ig heavy chain V-III region KOL Ig kappa chain V-I region Wes Ig heavy chain V-III region CAM FKBP1A:TacrolimusIGLV(23-?) Ig lambda chain V-I region NEW Ig lambda chain V-I region VOR Ig kappa chain V-II region FR CALM1Ig lambda chain V-II region TOG Ig kappa chain V-I region AG IGKV3D-20 Ig kappa chain V-I region AG ATPIg heavy chain V-I region HG3 26S proteasomePTPN6 IGHV1-2 p-S177,S181-IKBKB ADPIg lambda chain V-I region NEWM UBC(1-76) IGKV2D-30 IGLC6 Ig heavy chain V-III region JON Ig heavy chain V-I region HG3 Ig heavy chain V-III region DOB Ig lambda chain V-IV region Bau Ig kappa chain V-III region VG Ig lambda chain V region 4A IGKC Ig kappa chain V-III region POM Ig heavy chain V-III region WEA Ig kappa chain V-II region RPMI 6410 IGKV1-5(23-?) Ig lambda chain V-II region BOH MALT1Ig heavy chain V-II region WAH Ig heavy chain V-III region TRO Ig kappa chain V-I region AG p-T133-RASGRP3 Ig heavy chain V-I region EU Ig lambda chain V-I region HA I(1,4,5)P3 Ig heavy chain V-III region BRO Ig lambda chain V-I region VOR Ig lambda chain V-I region NEW Ig kappa chain V-I region DEE Activated PKC betaIg lambda chain V-II region TOG Ig heavy chain V-III region BRO Ig kappa chain V-I region Gal IGLC6 IGKV4-1(21-?) Ig heavy chain V-II region WAH IGHV(1-?) Ig lambda chain V-I region NEW p-S32,S36-NFKBIA PSME4 PTPN6:p-Y762,807,822-CD22:Antigen:p-BCRUBC(229-304) Antigen CHUK IGKV1-12 p-14S-NFATC2 UBC(533-608) NFKB1(1-433) PSMD13 Ig heavy chain V-III region DOB Ig kappa chain V-I region DEE IGKV2-28 CARD11 IGKV2-28 IGHV(1-?) IGKV3D-20 Ig kappa chain V-I region AG Tacrolimus RASGRP1 PSMD11 Ig lambda chain V-IV region Hil PSMD10 p-BCL10 Ig lambda chain V-II region TOG Ig kappa chain V-I region AU UBC(381-456) PSMB5 IGLC2 IGLC1 Ig kappa chain V-I region Wes Ig kappa chain V-III region B6 Ca2+ Ig kappa chain V-I region DEE UBC(609-684) Ig lambda chain V-II region BOH Ig kappa chain V-I region HK101 Ig kappa chain V-I region AU ITPR3 IGHM Ig kappa chain V-III region VG Ig lambda chain V-IV region Kern Ig heavy chain V-III region JON Ig lambda chain V-IV region Kern NAD+ Ig kappa chain V-I region BAN IGLC7 Ig heavy chain V-III region BRO Ig lambda chain V-II region BOH Ig heavy chain V-II region WAH Zn2+ IGLC3 IGLC2 p-S157,S161-NFKBIE RPS27A(1-76) Ig kappa chain V-II region RPMI 6410 Ig kappa chain V-I region BAN Ig lambda chain V-III region LOI CD22:Antigen:p-BCRIg kappa chain V-II region Cum Ig lambda chain V-I region NEW IGHV(1-?) Ig heavy chain V-III region WEA Fe3+ Ig heavy chain V-II region OU PI(4,5)P2p-Y196,Y207-CD79B Ig heavy chain V-II region ARH-77 Ig heavy chain V-I region HG3 PIK3R1 Ig lambda chain V-IV region Hil IGLC6 Ig kappa chain V-I region HK101 Ig kappa chain V-II region RPMI 6410 Ig lambda chain V-I region NEW IGLC2 RELA Ub-21,22-p-S32,S36-NFKBIA Ig kappa chain V-I region BAN Ig heavy chain V-II region NEWM Ig heavy chain V-III region WEA Ig heavy chain V-III region BUT Ig kappa chain V region EV15 p-Y188,Y199-CD79A IgH heavy chain V-III region VH26 precursor Ig lambda chain V-III region LOI Ig heavy chain V-I region HG3 Ig kappa chain V-III region VG SHC1-2,SHC1-3p-6Y-SYK IGHM Ig lambda chain V-I region VOR Ig lambda chain V-II region BOH p-12S-NFATC1 SKP1 Ig heavy chain V-II region ARH-77 Ig heavy chain V-III region DOB Ig lambda chain V-IV region Hil Ig kappa chain V-III region POM p-4Y-PIK3AP1 MALT1 Ig heavy chain V-II region MCE Ig kappa chain V-III region POM IGLC7 NF-kappaBp50,p65,c-Rel dimerIg heavy chain V-III region WEA PSMD14 DAGSTIM1 IGLC3 IGLC1 Ig heavy chain V-II region MCE Ig heavy chain V-II region ARH-77 IGKV2D-30 ORAI1 NFKBIB BLK-like proteinsIg lambda chain V region 4A RELA p-Y188,Y199-CD79A ADPIGLC3 DephosphorylatedNFATC1,2,3Ig heavy chain V-III region BRO IGKV2-28 PIK3R1 Ig lambda chain V-II region NEI IGKV1-12 PIK3CD PSMC6 IGLC7 p21 RAS:GTPPSMD12 Ig heavy chain V-II region MCE IGLC3 UBC(153-228) Ig kappa chain V-I region Wes HRAS NF-kappaBp50,p65,c-Rel dimerIGHD IGHD SYK BCAP SignalosomeIg kappa chain V-I region Wes p-13S-NFATC3 Ig heavy chain V-II region MCE Ig lambda chain V-II region MGC Ig lambda chain V-I region VOR IGHV1-2 Ig kappa chain V-I region AU PI(4,5)P2Ig kappa chain V-I region BAN Antigen Ig kappa chain V-I region BAN IGHV1-2 Ig heavy chain V-I region EU IGKV4-1(21-?) STIM1 DimerUBA52(1-76) IGLC1 PIK3R1 ITPR2 PSME2 IGLC3 IGHV1-2 PSMC2 Ig kappa chain V-I region AU IGKV2-28 Ig lambda chain V-III region LOI PSMA1 Ig lambda chain V-VI region AR IGHV(1-?) PIP3 activates AKTsignalingIGKV1-12 CBLB Ig kappa chain V-II region Cum Ig heavy chain V-III region KOL Ig kappa chain V-I region AG NCK1 p-T184-RASGRP1 Ig kappa chain V-I region Daudi Ig heavy chain V-III region TRO PSMD1 RASGRP1,3p-CARMA1:MALT1:p-BCL10IGKV4-1(21-?) Ig lambda chain V-I region HA Ig kappa chain V-III region POM IGLC7 Ig lambda chain V-IV region Bau CHUK IGLC7 Ig kappa chain V region EV15 Ig lambda chain V-I region NEWM p21 RAS:GDPIg heavy chain V-III region BRO Ig kappa chain V-II region RPMI 6410 Ig kappa chain V-II region RPMI 6410 Ca2+ Ig heavy chain V-III region KOL IGHV(1-?) PSMD8 IGLC6 Ig kappa chain V-II region RPMI 6410 CD79A I(1,4,5)P3Ig lambda chain V-II region TOG Ig heavy chain V-III region WEA IGHD PSMD3 (BTRC:CUL1:SKP1),(FBXW11:CUL1:SKP1)STIM1 p-CARMA1 Oligomerp-Y188,Y199-CD79A p-Y239,Y240,Y317-SHC1-2 p-Y188,Y199-CD79A Ig kappa chain V-I region BAN Ig kappa chain V-I region Wes IGKV2D-30 PSMD6 PSMD2 IGKV2D-30 IGKV2D-30 Ig lambda chain V-IV region Bau Ig heavy chain V-III region JON IGHD Ig heavy chain V-III region CAM Ig lambda chain V-III region SH Ig kappa chain V-II region RPMI 6410 Ig kappa chain V-III region B6 Ig lambda chain V-IV region Bau Ca2+ BTRC UBB(1-76) p-S257-NFATC1 IGLC6 IGLC7 IGKV4-1(21-?) Ig heavy chain V-I region HG3 IKBKG PIK3CD Ig kappa chain V-I region Daudi Ig kappa chain V-I region AG Ig kappa chain V-III region VG Ig heavy chain V-I region HG3 Ig heavy chain V-II region NEWM Ig heavy chain V-III region KOL p-S19,S23-NFKBIB p-Y762,807,822-CD22:Antigen:p-BCRIg kappa chain V-III region VG NRAS Ig lambda chain V-I region NEWM IGHD Antigen IGKV1-5(23-?) VAV1 SKP1 STIM1:CalciumNAc-CD22homo-oligomerUBB(77-152) IGLC3 Ig kappa chain V-I region Gal AHCYL1 PPP3R1 Ig lambda chain V-III region SH Ig heavy chain V-II region WAH Ig lambda chain V-IV region Hil Ig lambda chain V-III region LOI Ig lambda chain V-IV region Bau Zn2+ Ig kappa chain V region EV15 IGKV2D-30 Ig kappa chain V-III region POM NFKBIA Ig lambda chain V-I region NEWM Ig lambda chain V-IV region Bau Ig heavy chain V-I region EU PSMD5 IgH heavy chain V-III region VH26 precursor Ig kappa chain V-III region POM IGKV3D-20 Ig heavy chain V-I region EU IGKV1-12 p-Y196,Y207-CD79B Antigen:BCRHRAS IGLC7 IGKV1-12 IGKV4-1(21-?) IGLV(23-?) Ig kappa chain V-I region HK101 NF-kappa-Bp50,p65,c-Rel:p-IKBp-Y188,Y199-CD79A Ig lambda chain V region 4A IGLV(23-?) IGKVA18(21-?) PSMB2 Ig kappa chain V region EV15 Ig kappa chain V-I region Gal Ig kappa chain V-III region POM Ig kappa chain V-I region AG 16, 33, 415014, 81, 143871329, 13527, 44, 118, 12266, 156812, 58, 84, 10514223, 11232, 12067, 71, 88, 16116516, 3370667512013216711950, 67, 71, 88, 126867713450


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.

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Reactome-Converter 
Pathway is converted from Reactome ID: 983705
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Reactome version: 64
Reactome Author 
Reactome Author: May, Bruce

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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-BLNKComplexR-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)
BLK ProteinP51451 (Uniprot-TrEMBL)
BLK-like proteinsComplexR-HSA-3902518 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
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)
FYNProteinP06241 (Uniprot-TrEMBL)
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)
LYNProteinP07948 (Uniprot-TrEMBL)
MALT1 ProteinQ9UDY8 (Uniprot-TrEMBL)
MALT1ProteinQ9UDY8 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAP3K7ProteinO43318 (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)
SRMS ProteinQ9H3Y6 (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-BLNKArrowR-HSA-983703 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNKR-HSA-983704 (Reactome)
Antigen:p-BCR:p-SYK:p-BLNKmim-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)
BLK-like proteinsmim-catalysisR-HSA-983709 (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)
FYNmim-catalysisR-HSA-983709 (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)
LYNmim-catalysisR-HSA-5690702 (Reactome)
LYNmim-catalysisR-HSA-983709 (Reactome)
MALT1R-HSA-1168644 (Reactome)
MAP3K7R-HSA-1168637 (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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