Fc epsilon receptor (FCERI) signaling (Homo sapiens)

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29, 10542, 6312214, 12117, 57, 803, 66, 11316, 9651, 11959, 91, 125, 130, 1419, 32, 93, 13876126, 13184, 1079811, 38, 52, 77, 92...41, 10956, 82, 9910, 24, 37, 9511431, 11521, 11775, 106, 13565, 68, 10740, 907724, 39, 14046, 53, 81, 123, 13653, 73, 116, 1438, 84, 94, 11847, 60, 97, 12434, 88, 14415, 3336, 1049, 19, 613827, 35, 85, 12951336310, 24, 37, 9570, 86, 89139644, 20, 83, 13249, 62, 71, 100, 1081, 1112, 28, 7844, 45, 6894, 112, 137103, 12813, 54, 6979, 12318, 134endoplasmic reticulum lumennucleoplasmcytosolIGLV4-69(1-?) Ca2+ MAP3K7 Ig kappa chain V-II region Cum Ig heavy chain V-I region WOL IGLV11-55(1-?) IGLC1 Ig lambda chain V-VII region MOT ADPIg kappa chain V-I region Lay PLCG2 Ig kappa chain V-I region Mev Ig heavy chain V-I region Mot Ig heavy chain V-III region BUT Ig kappa chain V-IV region STH TRAF6 oligomer JUNIg lambda chain V-IV region Kern PSMD6 IGLV4-3(1-?) UBE2D1 PAK1 Ig kappa chain V-II region GM607 UBE2N CALM1 RAC1 Ig heavy chain V-I region WOL ATPUb-48-UBC(1-76) IGLC6 PSMB8 Ig kappa chain V-I region AG PSMA1 Ub-580-UBC(533-608) MyrG-p-Y420-FYN ATPIGHV(1-?) MALT1 oligomer p-Y172-VAV2 Ig kappa chain V-III region SIE Ig kappa chain V-I region Ni RasGRPs:DAG:Ca2+Ig heavy chain V-III region HIL Ig heavy chain V-III region BRO PPP3R1 DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomerNAD+ IGHE IGLV11-55(1-?) PPP3CA IGLV2-18(1-?) p-S63,S73-JUNp-Y239,Y240,Y317-SHC1-2 Ig kappa chain V-III region WOL Ig heavy chain V-II region WAH Ig heavy chain V-I region HG3 Ig kappa chain V-I region WEA PSMA6 LAT2GRB2-1 Zn2+ Ig heavy chain V-III region KOL Ig kappa chain V-III region NG9 IGLC2 Ig lambda chain V-II region TOG Ig kappa chain V-I region HK101 Ig heavy chain V-II region MCE p-SYK/p-BTKIg heavy chain V-II region HE Ig lambda chain V-I region NEW Ig lambda chain V-I region MEM p-S552,S645-CARD11SOS1 p-13S-NFATC3 GAB2IGLV7-46(1-?) ADPPLCG2 Ig kappa chain V-I region WEA Ig lambda chain V-II region VIL p-Y113,Y128,Y145-LCP2 PSMA8 Ig kappa chain V-I region Ni IGLV2-11(1-?) RASGRP2 GRAP2 PSMD13 IGLV3-22(1-?) p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76PLCG1 Ig kappa chain V-III region HIC Ig heavy chain V-III region TIL Ig heavy chain V-III region WAS PPP3CA Ig kappa chain V-I region CAR Ig kappa chain V-II region RPMI 6410 ATPATPIg heavy chain V-III region BUR Ig kappa chain V-I region Hau GRB2-1 Ig heavy chain V-III region TUR IGLV7-46(1-?) GRB2-1:SOS1GTPPLCG1 IGLV8-61(1-?) Ig kappa chain V-I region Ka Ig lambda chain V-I region BL2 Ig lambda chain V-VI region AR IGLC3 Ig lambda chain V-VII region MOT PSMC6 VAV3 Ig kappa chain V-II region FR IGKV1-5(23-?) Ig heavy chain V-I region HG3 ADPIKBKG VAV2 Ig heavy chain V-III region ZAP Ig kappa chain V-IV region Len p-S257-NFATC1 Ig heavy chain V-III region GAL PSMC5 Clusteredp:LYN:p-FCERI:IgE:allergin:p-6Y-SYKIg lambda chain V-I region HA Ig heavy chain V-III region CAM Ig lambda chain V-IV region Bau Ig lambda chain V-I region NEWM PSME4 IGLV(23-?) Ig kappa chain V-III region GOL Ig heavy chain V-II region ARH-77 PI(3,4,5)P3 Ig kappa chain V-I region Mev Ig kappa chain V-III region NG9 p-T202,Y204-MAPK3 Ig lambda chain V-IV region MOL Ig heavy chain V-III region BRO Ig kappa chain V-I region Gal p-S243-NFATC2 Ig kappa chain V-I region Walker Ig kappa chain V-II region Cum Ig heavy chain V-III region WEA IGLV11-55(1-?) Ig heavy chain V-III region TRO Ig kappa chain V-I region Kue IGLV10-54(1-?) p-Y90-PKC-theta:DAGp-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3Ig lambda chain V-II region BO PI(3,4,5)P3SHC1-2PLCG1 ADPPLCG2 Ig lambda chain V-IV region MOL Ig kappa chain V-III region SIE IGLC3 Zn2+ Ig lambda chain V-II region BOH Ig kappa chain V-III region Ti Ig lambda chain V-IV region X Ig kappa chain V-III region POM ATPp-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3KIg kappa chain V-I region EU Ig heavy chain V-III region GAL ATPGRAP2 p-6Y-SYK Ig kappa chain V-II region FR p-CARMA1 oligomer Ig lambda chain V-I region BL2 p-5Y-LAT-2 Ig heavy chain V-III region TEI p-Y174-VAV1 Ig kappa chain V-I region Kue p-Y239,Y240,Y317-SHC1-2 FCERI:IgE:allerginaggregateVAV2 Ig heavy chain V-III region NIE Ig heavy chain V-I region SIE GRB2-1 Ig heavy chain V-I region Mot Ig heavy chain V-III region BRO Ig lambda chain V-V region DEL Ig kappa chain V-IV region STH IGKV1-5(23-?) TAB1 CHUK Ig heavy chain V-II region WAH PLCG1 Ig lambda chain V-VI region SUT ATPPSMD2 VAV3 Ig kappa chain V-I region BAN PLCG1 Ig heavy chain V-III region JON IGLV1-44(1-?) ADPVAV1 TEC,BTK,ITK,(TXK)TAB2 p-5Y-LAT:p-SHC1:GRB2:SOS1Ig kappa chain V-I region OU IGLV4-60(1-?) SOS1 Ig lambda chain V-II region BO Ig heavy chain V-III region GA ADPCa2+ Ig lambda chain V-VII region MOT ATPIg heavy chain V-III region LAY p-S257,T261-MAP2K4 Ig kappa chain V-I region Bi ATPIGLC2 Ig lambda chain V-III region SH ATPIg heavy chain V-II region COR Ig lambda chain V-IV region Hil PSMD9 ATPp-S271,T275-MAP2K7 IgH heavy chain V-III region VH26 precursor Ig heavy chain V-III region WAS ATPIg lambda chain V-II region WIN p-Y113,Y128,Y145-LCP2 Ig lambda chain V-I region NIG-64 Ig lambda chain V-II region WIN Ig lambda chain V-IV region Hil Ig kappa chain V-I region Scw p-S32,S36-NFKBIA Ig lambda chain V-IV region MOL Ig lambda chain V region 4A Ig kappa chain V-III region CLL PLCG1 IGLC2 Ig lambda chain V-III region SH Ig heavy chain V-III region TRO Ig kappa chain V-I region AG Ig lambda chain V-II region MGC PI(3,4,5)P3 Ig heavy chain V-I region EU Ig heavy chain V-III region KOL Ig heavy chain V-I region SIE Ig kappa chain V-III region HIC ITPR2 Ig heavy chain V-I region EU IGLV4-60(1-?) p-Y239,Y240,Y317-SHC1-2 p-Y223,Y551-BTK Ig heavy chain V-III region TIL p-Y113,Y128,Y145-LCP2 PI(3,4)P2 p-Y551-BTK IgH heavy chain V-III region VH26 precursor PLCG1 Ig lambda chain V region 4A PKC-theta (open):DAGRASGRP2 Ig kappa chain V-III region CLL IGLV3-16(1-?) Ig heavy chain V-III region GAL p-Y1400,Y1412-MAP3K1Ig heavy chain V-III region DOB GTPRELA K63polyUb TRAF6 PSMA3 Ig lambda chain V-VI region AR Ig heavy chain V-III region JON Ig lambda chain V-I region WAH Ig kappa chain V-I region AU Ig kappa chain V-II region Cum Ig lambda chain V-VI region AR IGLV4-69(1-?) PSMB2 SOS1 PAK2 Ig heavy chain V-III region TEI IKKA:IKBKB:IKBKGp-Y239,Y240,Y317-SHC1-2 IGKVA18(21-?) Ig heavy chain V-II region DAW p-FCERI aggregate Ig lambda chain V-II region NIG-84 Ig kappa chain V-I region Wes Ig heavy chain V-II region OU GRB2-1 p-5Y-LAT-2 ITPR3 VAV1 Ig kappa chain V-I region Ni p-T325,T331,S362,S374-FOS FCER1G p-6Y-SYK Ig lambda chain V-VI region AR PLCG2 Ig kappa chain V-IV region JI Ig lambda chain V-I region NEW GRAP2 PRKCQ ADPIg kappa chain V-II region MIL Ig lambda chain V-IV region Hil ATPIg lambda chain V-IV region Bau IGKV1-5(23-?) Ig lambda chain V-VI region EB4 Ig kappa chain V-I region WAT VAV2 PSMD4 ATPMAPK8 TAB2 Ig heavy chain V-III region DOB PLCG1 p-Y519-TEC Ca2+Ig lambda chain V-II region BOH p-Y90,T219,T538,S676,S695-PRKCQ p-S32,36-IkB-alpha:NF-kB complexPI(3,4,5)P3 Ig kappa chain V-I region Gal IKBKB Fe3+ GRAP2 GRAP2 Ig lambda chain V-VI region EB4 p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2K63polyUb TRAF6 DAGsIGKC SOS1 Ig kappa chain V-I region Rei Ig lambda chain V-III region LOI Ig lambda chain V-IV region Kern Ig kappa chain V-I region BAN Ig heavy chain V-III region DOB TAB3 PSMD14 Ig kappa chain V-I region Wes IGLV4-60(1-?) Ig kappa chain V-III region IARC/BL41 p-T,Y-MAPK8 Ig kappa chain V-III region HAH IGLV5-45(1-?) p21 RAS:GDPAllergin IGHV(1-?) p-Y239,Y240,Y317-SHC1-2 Ig kappa chain V-I region WAT GRAP2 IGLV3-12(1-?) PhosphorylatedNFATC1,2,3PI(3,4,5)P3 GRB2-1 Ig kappa chain V-I region Rei Ig kappa chain V-III region HIC Ig kappa chain V-I region Daudi I(1,4,5)P3 IGHV7-81(1-?) p-5Y-LAT-2GDPMALT1 PSMC4 Allergin Ig heavy chain V-II region COR p-Y113,Y128,Y145-LCP2 p-Y396-LYN Ig heavy chain V-I region EU Ig kappa chain V-I region OU Ig lambda chain V-I region HA Ubc13:UBE2V1Ub-276-UBC(229-304) Ig heavy chain V-III region KOL IGLV5-37(1-?) Ig heavy chain V-I region WOL Ig lambda chain V-I region NIG-64 p-Y173-VAV3 Ig heavy chain V-III region BUT Ig kappa chain V-II region GM607 Ig heavy chain V-I region ND IGLC3 TEC p-Y239,Y240,Y317-SHC1-2 PSMB9 p-5Y-LAT-2 Ig heavy chain V-II region HE p-Y90,T219,T538,S676,S695-PRKCQ Ig lambda chain V-I region NEWM Ig kappa chain V-I region Lay Ig lambda chain V-II region TRO IGLV3-25(1-?) GDP Ig lambda chain V-IV region Bau Ig kappa chain V-IV region B17 RELA Ub-352-UBC(305-380) Ig heavy chain V-III region CAM Ig heavy chain V-III region JON UBE2V1 Ig heavy chain V-I region SIE IgH heavy chain V-III region VH26 precursor Ig heavy chain V-II region MCE DAGsDAGs Ig lambda chain V-II region NEI Ig heavy chain V-I region HG3 ATPBCL10 Ig kappa chain V-II region MIL PSMB4 p-Y113,Y128,Y145-LCP2 Ig kappa chain V-I region Scw p-T221,Y223-MAPK10 p-Y206,Y519-TEC IGLV1-40(1-?) IGLV2-18(1-?) Ig lambda chain V-IV region X Ig kappa chain V-I region Gal Ig kappa chain V-I region EU p-Y239,Y240,Y317-SHC1-2 Ig lambda chain V-II region MGC Ig heavy chain V-II region OU Ub-200-UBC(153-228) RELA p-Y239,Y240,Y317-SHC1-2 GAB2 PI(3,4,5)P3IGLV3-12(1-?) PSMB10 Ig heavy chain V-I region SIE Ig lambda chain V region 4A TEC Ig lambda chain V-I region HA p-Y420-TXK IGLV7-43(1-?) Ig kappa chain V-III region HIC p-5Y-LAT-2 Ig heavy chain V-III region BRO Ig lambda chain V-V region DEL Ig lambda chain V-I region BL2 Ig lambda chain V-III region LOI Ig heavy chain V-I region HG3 Ig kappa chain V-I region CAR Ig kappa chain V-I region AG IgH heavy chain V-III region VH26 precursor IGLV1-44(1-?) IP3 receptorhomotetramerVAV2 IGLV3-12(1-?) Ig kappa chain V-IV region Len CALM1:4xCa2+PI(3,4,5)P3 IGKV4-1(21-?) p-CARMA1 oligomer Ig heavy chain V-II region SESS Ig lambda chain V-II region MGC Ig heavy chain V-I region HG3 Ig kappa chain V-I region WEA Zn2+ IGLV4-60(1-?) Ig kappa chain V-III region CLL Ig heavy chain V-III region KOL Ig kappa chain V-III region B6 Ig kappa chain V-III region Ti p-FCERI aggregate GRAP2 IGHE Ig kappa chain V-I region WEA Ig heavy chain V-I region ND Ig kappa chain V-I region Ka Ig kappa chain V-III region POM Ig lambda chain V-II region WIN Ig lambda chain V-II region NIG-58 IGLC1 Ig heavy chain V-III region LAY Ig lambda chain V-II region BUR TAB1 Ig kappa chain V-I region Ka Ig heavy chain V-III region GA Calcineurin (CaN)NFKB1(1-433) Ig kappa chain V-I region HK101 AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerGDP Ig heavy chain V-II region SESS p-Y239,Y240,Y317-SHC1-2 Ig heavy chain V-II region HE p-Y113,Y128,Y145-LCP2 p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAVIg lambda chain V-III region LOI Ig heavy chain V-II region OU p-Y239,Y240,Y317-SHC1-2 BTRC Ig lambda chain V-I region MEM Ig lambda chain V-II region BOH DAGs Ig kappa chain V-II region TEW Ig kappa chain V-I region Wes PDK1:PIP2,PIP3Ig lambda chain V-II region NEI Ig kappa chain V-III region IARC/BL41 Ig lambda chain V-IV region Kern LCP2 Ig heavy chain V-I region Mot Ig heavy chain V-III region TIL Ig lambda chain V-V region DEL Ig kappa chain V-I region Walker Ig kappa chain V-IV region B17 PSMD5 Ig kappa chain V-II region TEW IGLV5-37(1-?) Ig kappa chain V-III region B6 GRB2-1 Ig lambda chain V-V region DEL Ig heavy chain V-I region SIE p-Y396-LYN Ig heavy chain V-III region CAM Ig kappa chain V-I region Roy RasGRPsIg kappa chain V-I region Mev Ub-48-UBA52(1-76) GADS:SLP76ITPR:I(1,4,5)P3tetramerIg kappa chain V-II region GM607 p-5Y-LAT-2 Ig heavy chain V-III region DOB Ig lambda chain V-II region NIG-84 IGLV4-3(1-?) p-Y90,T219,T538,S676,S695-PRKCQ ITPR3 Ig kappa chain V-I region Roy MAP2K4Ig lambda chain V-II region BOH Ig heavy chain V-II region MCE Ig lambda chain V-III region SH Ig kappa chain V-I region DEE NRAS VAV1 RELA FCERI:IgE aggregate IGLV3-16(1-?) Ig lambda chain V-II region BUR MALT1 oligomer NFKB1(1-433) Ig kappa chain V-III region GOL Ig lambda chain V-I region WAH Allergin IGLC7 Ig lambda chain V-III region LOI Ig heavy chain V-II region ARH-77 TXK Ig kappa chain V-III region POM Ig heavy chain V-III region NIE p-5Y-PKC-theta:DAGIg kappa chain V-I region CAR Ig kappa chain V-I region Gal Ig lambda chain V-IV region Kern Ig lambda chain V-I region WAH IGLV2-18(1-?) p-S63,S73-JUN Ig kappa chain V-III region CLL Ig lambda chain V-II region TOG Ig kappa chain V-III region Ti Ig lambda chain V-II region BUR BCL10 p-Y239,Y240,Y317-SHC1-2 p-Y113,Y128,Y145-LCP2 NFKB1(1-433) Ig heavy chain V-I region Mot PLCG1 PAK1 Ig heavy chain V-III region KOL IGLV(23-?) IGKV1-5(23-?) CALM1 Ig lambda chain V-II region MGC Ig kappa chain V-III region NG9 Ig kappa chain V-I region Bi p-Y239,Y240,Y317-SHC1-2 PPP3CB Ig heavy chain V-III region TUR PSMB5 Ig heavy chain V-I region EU RASGRP4 p-Y90,T219,T538,S676,S695-PRKCQ Ig kappa chain V-IV region STH PI(3,4,5)P3 ATPITPR1 GRAP2 Ig kappa chain V-III region VG Ig kappa chain V-III region GOL IGKVA18(21-?) ADPIg kappa chain V-III region SIE Ig kappa chain V-II region FR p-14S-NFATC2 PIK3R2 IGLC1 LCP2 DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:activated TAK1 complexFCER1A Ig kappa chain V-I region Kue Ig kappa chain V-I region OU p-T221,Y223-MAPK10 K63polyUb-NEMO Ig heavy chain V-III region ZAP PPP3CB IGLV8-61(1-?) SKP1 p-4Y-PLCG2 Ig lambda chain V-II region TOG Ig heavy chain V-III region LAY IGLV(23-?) IGKV4-1(21-?) ADPIg heavy chain V-II region DAW Ig heavy chain V-II region COR Ig heavy chain V-III region GAL p-5Y-LAT-2 p-Y90,T219,T538,S676,S695-PRKCQ p-10Y-NTAL:p-SHC1:GRB2:SOSIg kappa chain V-IV region JI p-Y113,Y128,Y145-LCP2 Ig heavy chain V-III region BUT p-10Y-LAT2Ig kappa chain V-II region RPMI 6410 PSMD10 Ig kappa chain V-III region SIE Ig lambda chain V-IV region X PSMA5 IGLV2-23(1-?) Ig kappa chain V-I region Roy PSMB3 Ig kappa chain V-I region Rei Ub-504-UBC(457-532) Ig kappa chain V-III region VH Ig lambda chain V-III region LOI Ig heavy chain V-II region HE p-CARMA1 oligomer IGKC Ig lambda chain V-II region NEI DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3Ig kappa chain V-II region GM607 p-Y519-TEC Ig kappa chain V-I region Rei Allergin:p-LYN:p-FCERI:IgE aggregateIg kappa chain V-III region HAH IGLV3-16(1-?) p-S177,S181-IKKB:IKKA:pUb-NEMOPLCG2 p-T,Y-MAPK8 IGLV2-18(1-?) GTP IGLV3-27(1-?) SOS1 ADPIg kappa chain V-I region AU PSME3 Ig kappa chain V-I region Lay Ig lambda chain V-I region NEWM Ig heavy chain V-III region HIL IGLV3-25(1-?) PSME1 Ig kappa chain V-IV region STH K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexATPIg kappa chain V-I region HK101 BCL10 oligomer Ig kappa chain V-I region Bi I(1,4,5)P3 Ig lambda chain V-VII region MOT Ig lambda chain V-II region BUR ITPR3 ADPIg kappa chain V-I region Bi DAGs IGLC7 Ig lambda chain V-V region DEL p-Y173-VAV3 Ig kappa chain V-I region DEE Ig kappa chain V-IV region JI Ig kappa chain V-I region OU BTK Ig kappa chain V-I region EU IGLV1-36(1-?) Ig heavy chain V-III region POM TXK Ig kappa chain V-I region Kue IGLV10-54(1-?) Ig lambda chain V-II region MGC Ub-TRAF6 trimerbound to CBMcomplexADPIg lambda chain V-IV region Kern IGLV3-12(1-?) Ig kappa chain V-I region Hau Ig kappa chain V-II region TEW ATPp-2S-cJUN:p-2S,2T-cFOSIg heavy chain V-III region GAL IGLV5-45(1-?) IGLV3-22(1-?) p-Y90,T219,T538,S676,S695-PRKCQ Ig kappa chain V-I region BAN Ig heavy chain V-II region ARH-77 IGLV2-23(1-?) IGLV1-44(1-?) Ig heavy chain V-III region GA Ig kappa chain V-II region TEW Ig lambda chain V-I region WAH Ig lambda chain V-VI region NIG-48 NFAT:CaN:CaMPLCG2 Ig kappa chain V-II region MIL IGLV(23-?) Ig heavy chain V-III region ZAP Ig kappa chain V-III region VH IGLV3-16(1-?) Ig lambda chain V-III region SH Ig heavy chain V-III region TUR NFKB1(1-433) Ca2+ IGLV3-22(1-?) Ig lambda chain V-II region NIG-84 NF-kB complexIg kappa chain V-IV region JI MALT1 oligomer Ig kappa chain V-II region TEW SYKPLCG2 Ig kappa chain V-I region Scw Ig lambda chain V-II region NIG-84 Ig kappa chain V-III region VG PLCG2 IGHE IGLC3 Ig lambda chain V-IV region X Ig lambda chain V-II region TRO IGLV4-60(1-?) Ig kappa chain V-I region CAR p-Y172-VAV2 IGLV2-11(1-?) p-12S-NFATC1 Ig kappa chain V-III region VH IGHE Ig lambda chain V-II region TRO p-MAPK8/9/10Ig kappa chain V-III region GOL Ig heavy chain V-II region SESS Ig lambda chain V-I region HA Ig lambda chain V-II region NEI Ig heavy chain V-III region TRO Ig lambda chain V-II region BOH Ig lambda chain V-VI region WLT Ig lambda chain V-IV region Bau IGLV4-3(1-?) Ig lambda chain V-VI region NIG-48 Ig kappa chain V-III region VG p-Y512-ITK p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAVIGLV4-69(1-?) Ig kappa chain V-III region VG p-Y452,Y476,Y584-GAB2 Ig lambda chain V-VI region WLT IGLV8-61(1-?) PSMC2 IGKV4-1(21-?) Ig lambda chain V-II region BO DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomerIGLV1-44(1-?) Ig heavy chain V-III region GAL Ig kappa chain V-I region AU Ig lambda chain V-IV region MOL PI(3,4,5)P3ADPIGLV2-11(1-?) Ig heavy chain V-III region POM IGLV2-33(1-?) IGLV3-25(1-?) PIK3CA Ig heavy chain V-III region BUR MAP3K7 Ub-428-UBC(381-456) Ub-200-UBB(153-228) Ig kappa chain V-II region RPMI 6410 Ig lambda chain V-II region TRO SOS1 MALT1 oligomer Ig heavy chain V-II region WAH SOS1 SOS1 IGLV3-27(1-?) Ig heavy chain V-III region BUR p-5Y-LAT-2 Ig kappa chain V-I region Walker MALT1 oligomer IGLV3-12(1-?) Ig kappa chain V-I region Ni p-Y90,T219,T538,S676,S695-PRKCQ GRAP2 p-CARMA1 oligomer Ig kappa chain V-I region DEE Ig kappa chain V-II region GM607 IGLC3 p-Y90,T219,T538,S676,S695-PRKCQ IgH heavy chain V-III region VH26 precursor IkB(alpha):NF-kBcomplexIgH heavy chain V-III region VH26 precursor IGLV3-22(1-?) Ig lambda chain V-VI region NIG-48 GRB2-1 Ca2+Ig heavy chain V-III region NIE Ig lambda chain V-IV region Hil RAF/MAP kinasecascadep-S177,S181-IKBKB Ig kappa chain V-I region Walker Ig kappa chain V-I region EU Ig lambda chain V-II region VIL Ig heavy chain V-III region LAY NFKBIA ATPIg lambda chain V-II region NIG-58 Ig kappa chain V-I region DEE Ig heavy chain V-III region TIL p-Y206,Y519-TEC Allergin Ig kappa chain V-III region VG p-Y396-LYN Ig kappa chain V-I region Ka p-S144,T423-PAK1 p-S265-NFATC3 Ig kappa chain V-III region Ti Ub-48-RPS27A(1-76) p-5Y-LAT-2 IGLV5-37(1-?) PI(3,4,5)P3 Ig kappa chain V-III region POM Ig heavy chain V-II region NEWM IGKVA18(21-?) LYNIg lambda chain V-I region NIG-64 MAP3K1Ig lambda chain V-I region HA Ig heavy chain V-III region TUR IGLC7 Ig heavy chain V-II region OU Ca2+Ig lambda chain V-I region VOR IGLV1-40(1-?) PSMA2 Ig heavy chain V-III region POM NFAT:CaN:CaMVAV1 ADPIGLV5-45(1-?) Ig lambda chain V-II region BO PPP3R1 Ig heavy chain V-I region Mot ATPIGLV4-3(1-?) PI(3,4,5)P3 IGLC6 Ig kappa chain V-I region Scw PSMB7 Ig heavy chain V-III region GA p-T183,Y185-MAPK9 IGLV3-12(1-?) p-Y239,Y240,Y317-SHC1-2 Ig kappa chain V-I region WEA IGKV4-1(21-?) Ig lambda chain V-III region SH p-Y396-LYN p-T,Y MAPK dimersDAG:p-5Y-PKC-theta:CBM oligomer:TRAF6KRAS GDPADPIg lambda chain V-VI region WLT Ig heavy chain V-II region COR BCL10MAPK9 PSMB6 TAB2 Ig heavy chain V-II region WAH IGLV(23-?) IGLV3-27(1-?) IGLV2-11(1-?) IGLV11-55(1-?) Ig kappa chain V-III region GOL IGLC6 PI(3,4,5)P3 IGLV1-40(1-?) p-S552-CARD11 SOS1 IGKV4-1(21-?) Ig heavy chain V-I region SIE SOS1 IGHV(1-?) Ig kappa chain V-I region Mev Ig kappa chain V region EV15 Ig heavy chain V-II region NEWM GRAP2 Ig lambda chain V-VII region MOT PIK3R1 IGLV4-69(1-?) p-S257-NFATC1 Ig kappa chain V-III region VH Ig lambda chain V-II region WIN IGLC7 Ig kappa chain V-IV region B17 IGKC Ig kappa chain V-III region WOL Ig heavy chain V-III region KOL Ub-656-UBC(609-684) K63polyUbBCL10 oligomer Ig heavy chain V-III region WEA Ig kappa chain V-II region MIL VAV3 Ig kappa chain V-III region IARC/BL41 Ig kappa chain V-I region Ka p-Y91,Y420-TXK Ig lambda chain V-I region VOR DAGs Ig lambda chain V-IV region Bau p-S257,T261-MAP2K4Ig kappa chain V-III region WOL Ig heavy chain V-I region Mot Ig kappa chain V-III region WOL Ig kappa chain V-II region Cum p-Y113,Y128,Y145-LCP2 p-5Y-LAT-2 Ig lambda chain V-II region NIG-84 PI(3,4,5)P3IGLC1 Ig kappa chain V-I region Daudi Ig heavy chain V-III region WEA Ig heavy chain V-III region POM PI(4,5)P2MAP3K7 Ig heavy chain V-II region DAW IGHV(1-?) Ig heavy chain V-II region ARH-77 PLC gamma1,226S proteasomeGRB2-1 VAV1 Ig lambda chain V-IV region Bau GRB2-1 LCP2 IGLV11-55(1-?) Ig heavy chain V-III region HIL IGLV1-40(1-?) PI(3,4,5)P3 Ig heavy chain V-II region NEWM Ig kappa chain V-I region AU TRAF6 Ig lambda chain V-III region SH GRB2-1 Ig kappa chain V-III region NG9 Ig heavy chain V-II region NEWM Ig lambda chain V-VI region EB4 Allergin Ig lambda chain V-II region NEI PSMC1 IGLV4-3(1-?) IGLV4-3(1-?) Ig kappa chain V-IV region B17 Ig kappa chain V-IV region Len GRB2-1 IGLV3-25(1-?) p-Y239,Y240,Y317-SHC1-2 Ig lambda chain V-I region VOR IGLV2-18(1-?) Ig kappa chain V-III region CLL p-5Y-LAT-2 Ig kappa chain V-III region SIE Ig heavy chain V-III region BUT Ig heavy chain V-II region WAH VAV2 Ig lambda chain V-II region NEI Ig heavy chain V-III region WAS PPP3CB PPP3R1 Ig heavy chain V-II region ARH-77 Ig lambda chain V-II region BUR Ig heavy chain V-III region NIE HRAS Ig lambda chain V-I region EPS CUL1 Ig lambda chain V-VI region WLT p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3IGLV1-44(1-?) p-T183,Y185-MAPK9 IGHE IGLC2 IGLV1-40(1-?) PSMD7 p-SHC1:GRB2:SOSGRB2-1 IGLV4-69(1-?) Ig kappa chain V-IV region JI Ig lambda chain V-II region TOG Ig kappa chain V-I region AG Ig lambda chain V-II region TRO Ig heavy chain V-III region LAY Ig kappa chain V-II region GM607 Ig heavy chain V-II region COR Ig lambda chain V-II region NIG-58 DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1Ig kappa chain V-I region Lay CHUK Ig kappa chain V-I region CAR Ig kappa chain V-I region AU p-CARMA1 oligomer SOS1 Ig heavy chain V-III region ZAP FOSIg kappa chain V-III region Ti VAV2 Ig kappa chain V region EV15 Ig heavy chain V-III region WEA ADPIg kappa chain V-III region VH IGLV3-22(1-?) Ig lambda chain V-VI region EB4 Ig kappa chain V-I region AG SOS1 Ig heavy chain V-II region HE RAC1:GDPIg lambda chain V-I region EPS Ig kappa chain V-I region Scw Ig kappa chain V-III region B6 Ig heavy chain V-II region SESS Ig kappa chain V region EV15 ADPClusteredp:LYN:p-FCERI:IgE:allergin:SYKFCERI:IgEIg lambda chain V-I region VOR Ig kappa chain V-I region Roy Ig kappa chain V-III region WOL p-S271,T275-MAP2K7IGLV2-33(1-?) Ig kappa chain V-I region Bi Ig lambda chain V-VI region SUT p-S141,T402-PAK2 Ig heavy chain V-III region TEI KRAS p-Y420-TXK PI(3,4)P2 NF-kB complexIg lambda chain V-I region MEM GRB2-1 ITPR2 BCL10 oligomer IGLV3-16(1-?) Ig kappa chain V-III region CLL IGLV5-45(1-?) Ig heavy chain V-I region ND SCF-beta-TRCPp-Y396-LYN p-S552,S645-CARD11 DAG:p-5Y-PKC-theta:CBM oligomerPIK3CA Ig heavy chain V-II region ARH-77 p-FCERI aggregate ADPIg kappa chain V-I region Hau Ig kappa chain V-II region MIL Ig kappa chain V-I region Mev Ig kappa chain V-I region Scw IGHV7-81(1-?) Ig lambda chain V-II region BOH p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinasesIg kappa chain V-I region Hau RAC1 Ig lambda chain V-II region TOG Ig heavy chain V-III region GA p-Y91,Y420-TXK IGLV7-46(1-?) GRAP2 ADPIg heavy chain V-III region DOB Ig kappa chain V-III region HIC Ig lambda chain V-I region BL2 IGLV1-36(1-?) Ig lambda chain V-I region MEM IGLV3-25(1-?) Ig kappa chain V-I region OU Ig heavy chain V-III region JON IGLV5-45(1-?) Ig lambda chain V region 4A ATPp-4Y-PLCG1 IGKC Ig heavy chain V-II region MCE IGLV(23-?) PPiITPR1 VAV3 Ig lambda chain V-I region NEW Ub-124-UBC(77-152) Ig lambda chain V-I region NEWM PLCG2 Ig lambda chain V-VI region NIG-48 SOS1 Ig kappa chain V-I region Hau AllerginIg heavy chain V-III region WEA GRB2-1 Ig lambda chain V-I region NEW Ig kappa chain V-I region OU AMPIg lambda chain V-I region EPS Ig kappa chain V-I region AU Ig lambda chain V-II region VIL PSMB1 p-Y239,Y240,Y317-SHC1-2 Ig kappa chain V-III region IARC/BL41 Ig lambda chain V region 4A p-10Y-LAT2 Ig heavy chain V-I region WOL ATPIGLV7-46(1-?) IGLV2-11(1-?) Ig kappa chain V-I region Gal PSMD12 DAGs IGLC6 ITPR1 Ig kappa chain V-I region Lay Ig kappa chain V-I region DEE Ig kappa chain V-III region NG9 ITK ITPR2 IGLV5-45(1-?) p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3IGLC3 IGLV3-22(1-?) Ig lambda chain V-IV region MOL PLCG1 Ig lambda chain V-IV region X Ig lambda chain V-II region BO GRB2-1 UBE2D2 IGHV7-81(1-?) Ig lambda chain V-V region DEL IGHV7-81(1-?) Ig kappa chain V-I region BAN Ig lambda chain V-II region NIG-58 Ig kappa chain V-I region Wes IGLV7-43(1-?) Ig lambda chain V-I region WAH PI(3,4,5)P3 DAGs Calcineurin:Calmodulin (CaN:CaM)BCL10:MALT1SOS1 Ig lambda chain V-II region VIL VAV2 CALM1 Ig kappa chain V-I region Daudi Ig lambda chain V-II region VIL TAB3 IGLV2-11(1-?) CARD11ITK Ig lambda chain V-VI region SUT IGKVA18(21-?) PLCG2 Ig lambda chain V-II region MGC p-CARMA1 oligomer MALT1 IGLV2-33(1-?) Ig lambda chain V-I region MEM IGLC6 VAV1 SOS1 Ig heavy chain V-II region WAH Ig lambda chain V-I region NIG-64 Ig heavy chain V-III region ZAP IGLV7-43(1-?) IGLC7 DAGs Ig lambda chain V-I region EPS p-10Y-NTAL:p-SHC1:GRB2:SOS:GAB2p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGIg lambda chain V region 4A p-Y239,Y240,Y317-SHC1-2ATPAHCYL1 IGLC2 p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTPIGKVA18(21-?) PLCG2 IGLV2-23(1-?) p-Y90-PRKCQ Ig heavy chain V-III region TRO Ig heavy chain V-III region TIL DAGs p-BCL10 Ig heavy chain V-II region MCE Ig kappa chain V-I region BAN TRAF6IGLV1-36(1-?) ADPIGKVA18(21-?) PSMB11 Ig kappa chain V-IV region JI Ig lambda chain V-II region BUR MAP2K7IGLV4-69(1-?) CALM1IGLV5-37(1-?) Ig kappa chain V-III region VH BCL10 oligomer Ig kappa chain V-I region CAR IGLV1-44(1-?) p-Y396-LYNp-T185,Y187-MAPK1 Ig kappa chain V-II region FR Ig heavy chain V-I region ND Ig kappa chain V-II region RPMI 6410 p-FCERI aggregate Ig kappa chain V-I region EU Ig heavy chain V-I region EU PAK2 Ig kappa chain V-I region BAN Ig heavy chain V-III region WEA Ig heavy chain V-III region BUT Ig kappa chain V-III region HAH p-2Y-PAKIg lambda chain V-VI region AR VAV3 Ig kappa chain V-I region Wes Ig kappa chain V-II region Cum Ig kappa chain V region EV15 Fe3+ SOS1 MAPK10 Ig heavy chain V-III region LAY Ig kappa chain V-III region NG9 K63polyUb TRAF6 SYK p-CARMA1 oligomer PSMD8 Ig heavy chain V-I region EU Ca2+ Ig lambda chain V-IV region Hil GRB2-1 Ig heavy chain V-III region BUR I(1,4,5)P3IGLV10-54(1-?) Ig heavy chain V-I region HG3 K48-UbIg kappa chain V-I region HK101 PiIg kappa chain V-IV region B17 Ig heavy chain V-III region BRO IGHV7-81(1-?) IGLV11-55(1-?) Ig kappa chain V-III region HAH DAGs Ig kappa chain V-III region B6 PSMA7 PLCG1 IGLV5-37(1-?) Ig kappa chain V region EV15 Ig kappa chain V-II region FR IGLV1-40(1-?) Ig kappa chain V-I region WEA IGLV3-27(1-?) Ig lambda chain V-I region BL2 IGLV2-33(1-?) Ig kappa chain V-IV region Len IGLV7-46(1-?) K48PolyUb-K21,22-p-S32,S36-IkBA Ig kappa chain V-I region Daudi Ig heavy chain V-III region WAS Ig heavy chain V-III region ZAP p-10Y-LAT2 IGLV8-61(1-?) Ub-48-UBB(1-76) BCL10 oligomer Ig heavy chain V-I region WOL IGLV10-54(1-?) IGLV5-37(1-?) p-Y239,Y240,Y317-SHC1-2 IGLV7-43(1-?) MAPK8/9/10Ig lambda chain V-II region NIG-84 Ig heavy chain V-III region TRO PPP3CA Ig lambda chain V-I region BL2 Ig heavy chain V-III region CAM Ig lambda chain V-VI region AR IGKC ADPPI(3,4,5)P3 Ig lambda chain V-IV region MOL Ig lambda chain V-IV region Hil Ig kappa chain V-I region AG Ig kappa chain V-III region B6 IGLV2-23(1-?) PDPK1IGKV1-5(23-?) Ig heavy chain V-II region OU ATPK63polyUb TRAF6 Ig heavy chain V-III region TUR PDPK1 p-Y174-VAV1 Ig lambda chain V-II region TRO Zn2+ DAGs VAV3 Ig heavy chain V-II region NEWM VAV1 p-5Y-LAT-2 RASGRP1 Ig heavy chain V-III region TIL Ig lambda chain V-II region NIG-58 Ig kappa chain V-III region WOL IGLV2-18(1-?) Ig lambda chain V-I region NEWM Ig kappa chain V-I region Lay Ig heavy chain V-III region NIE PIP3 activates AKTsignalingIg lambda chain V-VI region SUT GTP BCL10 oligomer Ig kappa chain V-I region HK101 IGLV8-61(1-?) PSMF1 Ig heavy chain V-III region BUT p-CARMA1 oligomer Ig heavy chain V-III region BRO IGLC6 Ig kappa chain V-III region GOL Ig kappa chain V-III region HAH p21 RAS:GTPIg heavy chain V-III region TRO Ig kappa chain V-II region Cum CHUK Ig kappa chain V-II region FR Ub-124-UBB(77-152) Ig lambda chain V-II region TOG IGLV2-23(1-?) p-Y174-VAV1 Ig kappa chain V-I region Daudi Ig heavy chain V-III region TEI IGLV2-23(1-?) PPP3CA Ig heavy chain V-III region POM SYK/FYNIg kappa chain V-I region Roy p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimerIg heavy chain V-III region GA SOS1 Ig heavy chain V-III region HIL NRAS Ig lambda chain V-VI region SUT Ig kappa chain V-I region DEE Ig lambda chain V-III region LOI Ig heavy chain V-III region DOB p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGIg lambda chain V-I region MEM Ig lambda chain V-II region WIN ATPIg kappa chain V-I region Daudi PSME2 Ig kappa chain V-I region Bi IGLV10-54(1-?) IGLV1-36(1-?) Ig heavy chain V-III region POM IGLV1-36(1-?) p-S177,S181-IKKB:IKKA:NEMOUBE2V1 Ig kappa chain V-III region B6 Ig kappa chain V-I region Wes Ig lambda chain V-I region VOR FBXW11 Ig lambda chain V-I region EPS Ig heavy chain V-III region CAM LAT-2PI(3,4,5)P3 Ig heavy chain V-II region DAW IGLV2-33(1-?) Ig lambda chain V-I region NIG-64 Ig kappa chain V-II region TEW IGLV3-16(1-?) Ig kappa chain V-I region WAT HRAS Ig heavy chain V-III region WAS Ig lambda chain V-II region VIL TAB1 Ig heavy chain V-I region WOL IGLV7-43(1-?) DAG:p-5Y-PKC-theta:CBM complexp-Y173-VAV3 Ig kappa chain V-I region Walker Ig kappa chain V-III region POM DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6Ca2+ Ig heavy chain V-I region ND Ig lambda chain V-VI region EB4 Ig heavy chain V-III region TEI VAV1,2,3IKBKG RASGRP1 RASGRP4 Ig lambda chain V-I region NIG-64 IGLV3-27(1-?) Ig lambda chain V-II region NIG-58 Ig kappa chain V-I region Hau Ig heavy chain V-II region SESS PSMD3 IGHV7-81(1-?) NFKB1(1-433) GRB2-1 Ig lambda chain V-I region EPS GTP IGLV8-61(1-?) Ig kappa chain V-IV region Len IGLC2 IGLV7-43(1-?) DAGs p-FCERI aggregate IGLV3-27(1-?) GRB2-1 Ig kappa chain V-I region Ka Ig lambda chain V-VI region NIG-48 MALT1 oligomer Ig heavy chain V-III region JON IGHV(1-?) Ig kappa chain V-III region HAH PPP3CB Ig kappa chain V-III region IARC/BL41 IGLV4-60(1-?) Ig kappa chain V-III region IARC/BL41 H2Op-Y90,T219,T538,S676,S695-PRKCQ Ig kappa chain V-I region Rei H2Op-S177,S181-IKBKB Ig heavy chain V-III region TEI p-5Y-LAT-2 Ig heavy chain V-II region MCE PIK3R2 PIK3CB Ig kappa chain V region EV15 Ig kappa chain V-I region Kue p-10Y-LAT2 GRAP2 Ig heavy chain V-III region HIL PSMA4 IGKV4-1(21-?) Ig kappa chain V-I region EU p-Y551-BTK Ig kappa chain V-III region Ti Ig kappa chain V-II region MIL Ig kappa chain V-I region WAT Ig heavy chain V-II region NEWM Ig kappa chain V-IV region STH Ig heavy chain V-II region HE PI(3,4,5)P3 IGKV1-5(23-?) CDC34 Ig kappa chain V-III region VG Ig kappa chain V-III region POM IGLV3-25(1-?) MALT1 Ig heavy chain V-II region COR DAGs Ig kappa chain V-II region RPMI 6410 IGLC1 ADPPAK dimerIg kappa chain V-III region HIC IGLC7 Ig kappa chain V-IV region Len p-MAPK8/9/10Ig lambda chain V-VI region NIG-48 SOS1 GRB2-1 Fe3+ p-10Y-LAT2 Ig heavy chain V-I region ND GRAP2 Ig lambda chain V-I region VOR Fe3+ RAC1 ADPIg kappa chain V-I region Mev Ig kappa chain V-I region Walker Ig kappa chain V-II region RPMI 6410 p-Y172-VAV2 Ig kappa chain V-IV region STH Ig lambda chain V-I region NEWM Ig lambda chain V-VII region MOT IGHV(1-?) PSMD1 Ig kappa chain V-I region HK101 p-5Y-LAT-2 Ig heavy chain V-II region DAW p-Y452,Y476,Y584-GAB2 p-T325,T331,S362,S374-FOSp-S265-NFATC3 Ig kappa chain V-I region WAT MS4A2 p-Y239,Y240,Y317-SHC1-2 p-Y239,Y240,Y317-SHC1-2 SOS1 Ig heavy chain V-III region TUR IGKC p-6Y-SYK ADPVAV3 Ig lambda chain V-II region WIN PRKQC closedconformationIg heavy chain V-III region JON PI(3,4)P2 IGHE PDPK1 Ig heavy chain V-III region NIE Ig lambda chain V-I region HA Ig kappa chain V-I region WAT Ig lambda chain V-VI region WLT p-Y512-ITK p-Y113,Y128,Y145-LCP2 IGLV7-46(1-?) UBE2N IGLV1-36(1-?) Allergin PI(4,5)P2Ig heavy chain V-III region BUR Ig lambda chain V-I region NEW PSMD11 PIK3CB IGLC1 Ig lambda chain V-IV region X p-MAP2K4/p-MAP2K7p-Y223,Y551-BTK Ubc13:UBE2V1p-Y180,Y512-ITK Ig lambda chain V-I region NEW Ig kappa chain V-I region Kue TAB1:TAB2,TAB3:TAK1Ig heavy chain V-II region DAW Ig kappa chain V-III region SIE Ig kappa chain V-I region Ni Ig lambda chain V-VI region WLT UBE2D2,UBE2D1,(CDC34)PPP3R1 ATPIg kappa chain V-IV region B17 Ig heavy chain V-II region OU Ig kappa chain V-I region Ni Ig lambda chain V-II region BO PIP3, PI(3,4)P2PSMC3 Ig heavy chain V-II region SESS Ig lambda chain V-IV region Kern IGLV2-33(1-?) RELA IGLV10-54(1-?) Ig heavy chain V-III region BUR Ig heavy chain V-III region WAS p-Y180,Y512-ITK Ig kappa chain V-I region Roy Ig kappa chain V-I region Rei Ig heavy chain V-III region HIL PIK3R1 PI3Kp-Y90,T219,T538,S676,S695-PRKCQ ADPIg lambda chain V-VI region SUT Ig kappa chain V-I region Gal CALM1 MALT1DAGs Ig heavy chain V-III region CAM TAB3 BTK Ig lambda chain V-I region WAH Ig lambda chain V-VI region EB4 p-S243-NFATC2 22227912022139225512013912012022226, 23, 25, 26, 30...1258222287139222213922


Description

Mast cells (MC) are distributed in tissues throughout the human body and have long been recognized as key cells of type I hypersensitivity reactions. They also play important roles in inflammatory and immediate allergic reactions. Activation through FCERI-bound antigen-specific IgE causes release of potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells (Borish & Joseph 1992, Amin 2012, Metcalfe et al. 1993). FCERI is a multimeric cell-surface receptor that binds the Fc fragment of IgE with high affinity. On mast cells and basophils FCERI exists as a tetrameric complex consisting of one alpha-chain, one beta-chain, and two disulfide-bonded gamma-chains, and on dendritic cells, Langerhans cells, macrophages, and eosinophils it exists as a trimeric complex with one alpha-chain and two disulfide-bonded gamma-chains (Wu 2011, Kraft & Kinet 2007). FCERI signaling in mast cells includes a network of signaling molecules and adaptor proteins. These molecules coordinate ultimately leading to effects on degranulation, eicosanoid production, and cytokine and chemokine production and cell migration and adhesion, growth and survival.
The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001). View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114731view16:21, 25 January 2021ReactomeTeamReactome version 75
113175view11:24, 2 November 2020ReactomeTeamReactome version 74
112403view15:34, 9 October 2020ReactomeTeamReactome version 73
101307view11:19, 1 November 2018ReactomeTeamreactome version 66
100844view20:51, 31 October 2018ReactomeTeamreactome version 65
100385view19:25, 31 October 2018ReactomeTeamreactome version 64
99932view16:09, 31 October 2018ReactomeTeamreactome version 63
99487view14:41, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99139view12:40, 31 October 2018ReactomeTeamreactome version 62
93828view13:39, 16 August 2017ReactomeTeamreactome version 61
93378view11:22, 9 August 2017ReactomeTeamreactome version 61
87447view13:46, 22 July 2016MkutmonOntology Term : 'Fc epsilon receptor mediated signaling pathway' added !
86464view09:18, 11 July 2016ReactomeTeamreactome version 56
83375view11:03, 18 November 2015ReactomeTeamVersion54
81548view13:05, 21 August 2015ReactomeTeamVersion53
77017view08:31, 17 July 2014ReactomeTeamFixed remaining interactions
76722view12:08, 16 July 2014ReactomeTeamFixed remaining interactions
76048view10:10, 11 June 2014ReactomeTeamRe-fixing comment source
75757view11:25, 10 June 2014ReactomeTeamReactome 48 Update
75107view14:05, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74754view08:50, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
AHCYL1 ProteinO43865 (Uniprot-TrEMBL)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerComplexR-HSA-5226920 (Reactome)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Allergin R-NUL-2454186 (Reactome)
Allergin:p-LYN:p-FCERI:IgE aggregateComplexR-HSA-2454232 (Reactome)
AllerginR-NUL-2454186 (Reactome)
BCL10 ProteinO95999 (Uniprot-TrEMBL)
BCL10 oligomer R-HSA-2685702 (Reactome)
BCL10:MALT1ComplexR-HSA-2685715 (Reactome)
BCL10ProteinO95999 (Uniprot-TrEMBL)
BTK ProteinQ06187 (Uniprot-TrEMBL)
BTRC ProteinQ9Y297 (Uniprot-TrEMBL)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CALM1:4xCa2+ComplexR-HSA-74294 (Reactome)
CALM1ProteinP62158 (Uniprot-TrEMBL)
CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
CDC34 ProteinP49427 (Uniprot-TrEMBL)
CHUK ProteinO15111 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Calcineurin (CaN)ComplexR-HSA-2025977 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ComplexR-HSA-2025947 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:SYKComplexR-HSA-2454243 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKComplexR-HSA-2454231 (Reactome)
DAG:p-5Y-PKC-theta:CBM complexComplexR-HSA-2685688 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomerComplexR-HSA-2685713 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6ComplexR-HSA-2685682 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3ComplexR-HSA-2685689 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:activated TAK1 complexComplexR-HSA-2685709 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6ComplexR-HSA-2685691 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomerComplexR-HSA-2685671 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomerComplexR-HSA-2685699 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1ComplexR-HSA-2685711 (Reactome)
DAGs MetaboliteCHEBI:18035 (ChEBI)
DAGsMetaboliteCHEBI:18035 (ChEBI)
FBXW11 ProteinQ9UKB1 (Uniprot-TrEMBL)
FCER1A ProteinP12319 (Uniprot-TrEMBL)
FCER1G ProteinP30273 (Uniprot-TrEMBL)
FCERI:IgE aggregate R-HSA-2685660 (Reactome)
FCERI:IgE:allergin aggregateComplexR-HSA-2454196 (Reactome)
FCERI:IgEComplexR-HSA-2454224 (Reactome)
FOSProteinP01100 (Uniprot-TrEMBL)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GADS:SLP76ComplexR-HSA-2424463 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRAP2 ProteinO75791 (Uniprot-TrEMBL)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1ComplexR-HSA-109797 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HRAS ProteinP01112 (Uniprot-TrEMBL)
I(1,4,5)P3 MetaboliteCHEBI:16595 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IGHE ProteinP01854 (Uniprot-TrEMBL)
IGHV(1-?) ProteinA2KUC3 (Uniprot-TrEMBL)
IGHV7-81(1-?) ProteinQ6PIL0 (Uniprot-TrEMBL)
IGKC ProteinP01834 (Uniprot-TrEMBL)
IGKV1-5(23-?) ProteinP01602 (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)
IGLV1-36(1-?) ProteinQ5NV67 (Uniprot-TrEMBL)
IGLV1-40(1-?) ProteinQ5NV69 (Uniprot-TrEMBL)
IGLV1-44(1-?) ProteinQ5NV81 (Uniprot-TrEMBL)
IGLV10-54(1-?) ProteinQ5NV86 (Uniprot-TrEMBL)
IGLV11-55(1-?) ProteinQ5NV87 (Uniprot-TrEMBL)
IGLV2-11(1-?) ProteinQ5NV84 (Uniprot-TrEMBL)
IGLV2-18(1-?) ProteinQ5NV65 (Uniprot-TrEMBL)
IGLV2-23(1-?) ProteinQ5NV89 (Uniprot-TrEMBL)
IGLV2-33(1-?) ProteinQ5NV66 (Uniprot-TrEMBL)
IGLV3-12(1-?) ProteinQ5NV85 (Uniprot-TrEMBL)
IGLV3-16(1-?) ProteinQ5NV64 (Uniprot-TrEMBL)
IGLV3-22(1-?) ProteinQ5NV75 (Uniprot-TrEMBL)
IGLV3-25(1-?) ProteinQ5NV90 (Uniprot-TrEMBL)
IGLV3-27(1-?) ProteinQ5NV91 (Uniprot-TrEMBL)
IGLV4-3(1-?) ProteinQ5NV61 (Uniprot-TrEMBL)
IGLV4-60(1-?) ProteinQ5NV79 (Uniprot-TrEMBL)
IGLV4-69(1-?) ProteinQ5NV92 (Uniprot-TrEMBL)
IGLV5-37(1-?) ProteinQ5NV68 (Uniprot-TrEMBL)
IGLV5-45(1-?) ProteinQ5NV82 (Uniprot-TrEMBL)
IGLV7-43(1-?) ProteinQ5NV80 (Uniprot-TrEMBL)
IGLV7-46(1-?) ProteinQ5NV83 (Uniprot-TrEMBL)
IGLV8-61(1-?) ProteinQ5NV62 (Uniprot-TrEMBL)
IKBKB ProteinO14920 (Uniprot-TrEMBL)
IKBKG ProteinQ9Y6K9 (Uniprot-TrEMBL)
IKKA:IKBKB:IKBKGComplexR-HSA-168113 (Reactome)
IP3 receptor homotetramerComplexR-HSA-169686 (Reactome)
ITK ProteinQ08881 (Uniprot-TrEMBL)
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-I region Mot ProteinP06326 (Uniprot-TrEMBL)
Ig heavy chain V-I region ND ProteinP01744 (Uniprot-TrEMBL)
Ig heavy chain V-I region SIE ProteinP01761 (Uniprot-TrEMBL)
Ig heavy chain V-I region WOL ProteinP01760 (Uniprot-TrEMBL)
Ig heavy chain V-II region ARH-77 ProteinP06331 (Uniprot-TrEMBL)
Ig heavy chain V-II region COR ProteinP01815 (Uniprot-TrEMBL)
Ig heavy chain V-II region DAW ProteinP01816 (Uniprot-TrEMBL)
Ig heavy chain V-II region HE ProteinP01818 (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 SESS ProteinP04438 (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 BUR ProteinP01773 (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 GA ProteinP01769 (Uniprot-TrEMBL)
Ig heavy chain V-III region GAL ProteinP01781 (Uniprot-TrEMBL)
Ig heavy chain V-III region HIL ProteinP01771 (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 LAY ProteinP01775 (Uniprot-TrEMBL)
Ig heavy chain V-III region NIE ProteinP01770 (Uniprot-TrEMBL)
Ig heavy chain V-III region POM ProteinP01774 (Uniprot-TrEMBL)
Ig heavy chain V-III region TEI ProteinP01777 (Uniprot-TrEMBL)
Ig heavy chain V-III region TIL ProteinP01765 (Uniprot-TrEMBL)
Ig heavy chain V-III region TRO ProteinP01762 (Uniprot-TrEMBL)
Ig heavy chain V-III region TUR ProteinP01779 (Uniprot-TrEMBL)
Ig heavy chain V-III region WAS ProteinP01776 (Uniprot-TrEMBL)
Ig heavy chain V-III region WEA ProteinP01763 (Uniprot-TrEMBL)
Ig heavy chain V-III region ZAP ProteinP01778 (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 Bi ProteinP01595 (Uniprot-TrEMBL)
Ig kappa chain V-I region CAR ProteinP01596 (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 EU ProteinP01598 (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 Hau ProteinP01600 (Uniprot-TrEMBL)
Ig kappa chain V-I region Ka ProteinP01603 (Uniprot-TrEMBL)
Ig kappa chain V-I region Kue ProteinP01604 (Uniprot-TrEMBL)
Ig kappa chain V-I region Lay ProteinP01605 (Uniprot-TrEMBL)
Ig kappa chain V-I region Mev ProteinP01612 (Uniprot-TrEMBL)
Ig kappa chain V-I region Ni ProteinP01613 (Uniprot-TrEMBL)
Ig kappa chain V-I region OU ProteinP01606 (Uniprot-TrEMBL)
Ig kappa chain V-I region Rei ProteinP01607 (Uniprot-TrEMBL)
Ig kappa chain V-I region Roy ProteinP01608 (Uniprot-TrEMBL)
Ig kappa chain V-I region Scw ProteinP01609 (Uniprot-TrEMBL)
Ig kappa chain V-I region WAT ProteinP80362 (Uniprot-TrEMBL)
Ig kappa chain V-I region WEA ProteinP01610 (Uniprot-TrEMBL)
Ig kappa chain V-I region Walker ProteinP04431 (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 GM607 ProteinP06309 (Uniprot-TrEMBL)
Ig kappa chain V-II region MIL ProteinP01616 (Uniprot-TrEMBL)
Ig kappa chain V-II region RPMI 6410 ProteinP06310 (Uniprot-TrEMBL)
Ig kappa chain V-II region TEW ProteinP01617 (Uniprot-TrEMBL)
Ig kappa chain V-III region B6 ProteinP01619 (Uniprot-TrEMBL)
Ig kappa chain V-III region CLL ProteinP04207 (Uniprot-TrEMBL)
Ig kappa chain V-III region GOL ProteinP04206 (Uniprot-TrEMBL)
Ig kappa chain V-III region HAH ProteinP18135 (Uniprot-TrEMBL)
Ig kappa chain V-III region HIC ProteinP18136 (Uniprot-TrEMBL)
Ig kappa chain V-III region IARC/BL41 ProteinP06311 (Uniprot-TrEMBL)
Ig kappa chain V-III region NG9 ProteinP01621 (Uniprot-TrEMBL)
Ig kappa chain V-III region POM ProteinP01624 (Uniprot-TrEMBL)
Ig kappa chain V-III region SIE ProteinP01620 (Uniprot-TrEMBL)
Ig kappa chain V-III region Ti ProteinP01622 (Uniprot-TrEMBL)
Ig kappa chain V-III region VG ProteinP04433 (Uniprot-TrEMBL)
Ig kappa chain V-III region VH ProteinP04434 (Uniprot-TrEMBL)
Ig kappa chain V-III region WOL ProteinP01623 (Uniprot-TrEMBL)
Ig kappa chain V-IV region B17 ProteinP06314 (Uniprot-TrEMBL)
Ig kappa chain V-IV region JI ProteinP06313 (Uniprot-TrEMBL)
Ig kappa chain V-IV region Len ProteinP01625 (Uniprot-TrEMBL)
Ig kappa chain V-IV region STH ProteinP83593 (Uniprot-TrEMBL)
Ig lambda chain V region 4A ProteinP04211 (Uniprot-TrEMBL)
Ig lambda chain V-I region BL2 ProteinP06316 (Uniprot-TrEMBL)
Ig lambda chain V-I region EPS ProteinP06888 (Uniprot-TrEMBL)
Ig lambda chain V-I region HA ProteinP01700 (Uniprot-TrEMBL)
Ig lambda chain V-I region MEM ProteinP06887 (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 NIG-64 ProteinP01702 (Uniprot-TrEMBL)
Ig lambda chain V-I region VOR ProteinP01699 (Uniprot-TrEMBL)
Ig lambda chain V-I region WAH ProteinP04208 (Uniprot-TrEMBL)
Ig lambda chain V-II region BO ProteinP01710 (Uniprot-TrEMBL)
Ig lambda chain V-II region BOH ProteinP01706 (Uniprot-TrEMBL)
Ig lambda chain V-II region BUR ProteinP01708 (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 NIG-58 ProteinP01713 (Uniprot-TrEMBL)
Ig lambda chain V-II region NIG-84 ProteinP04209 (Uniprot-TrEMBL)
Ig lambda chain V-II region TOG ProteinP01704 (Uniprot-TrEMBL)
Ig lambda chain V-II region TRO ProteinP01707 (Uniprot-TrEMBL)
Ig lambda chain V-II region VIL ProteinP01711 (Uniprot-TrEMBL)
Ig lambda chain V-II region WIN ProteinP01712 (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-IV region MOL ProteinP06889 (Uniprot-TrEMBL)
Ig lambda chain V-IV region X ProteinP01716 (Uniprot-TrEMBL)
Ig lambda chain V-V region DEL ProteinP01719 (Uniprot-TrEMBL)
Ig lambda chain V-VI region AR ProteinP01721 (Uniprot-TrEMBL)
Ig lambda chain V-VI region EB4 ProteinP06319 (Uniprot-TrEMBL)
Ig lambda chain V-VI region NIG-48 ProteinP01722 (Uniprot-TrEMBL)
Ig lambda chain V-VI region SUT ProteinP06317 (Uniprot-TrEMBL)
Ig lambda chain V-VI region WLT ProteinP06318 (Uniprot-TrEMBL)
Ig lambda chain V-VII region MOT ProteinP01720 (Uniprot-TrEMBL)
IgH heavy chain V-III region VH26 precursor ProteinP01764 (Uniprot-TrEMBL)
IkB(alpha):NF-kB complexComplexR-HSA-193938 (Reactome)
JUNProteinP05412 (Uniprot-TrEMBL)
K48-UbComplexR-HSA-912722 (Reactome) The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexComplexR-HSA-5607697 (Reactome)
K48PolyUb-K21,22-p-S32,S36-IkBA ProteinP25963 (Uniprot-TrEMBL)
K63polyUb TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
K63polyUb-NEMO ProteinQ9Y6K9 (Uniprot-TrEMBL)
K63polyUbR-HSA-450152 (Reactome)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LAT-2ProteinO43561-2 (Uniprot-TrEMBL)
LAT2ProteinQ9GZY6 (Uniprot-TrEMBL)
LCP2 ProteinQ13094 (Uniprot-TrEMBL)
LYNProteinP07948 (Uniprot-TrEMBL)
MALT1 ProteinQ9UDY8 (Uniprot-TrEMBL)
MALT1 oligomer R-HSA-2685673 (Reactome)
MALT1ProteinQ9UDY8 (Uniprot-TrEMBL)
MAP2K4ProteinP45985 (Uniprot-TrEMBL)
MAP2K7ProteinO14733 (Uniprot-TrEMBL)
MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
MAP3K7 ProteinO43318 (Uniprot-TrEMBL)
MAPK10 ProteinP53779 (Uniprot-TrEMBL)
MAPK8 ProteinP45983 (Uniprot-TrEMBL)
MAPK8/9/10ComplexR-HSA-450289 (Reactome)
MAPK9 ProteinP45984 (Uniprot-TrEMBL)
MS4A2 ProteinQ01362 (Uniprot-TrEMBL)
MyrG-p-Y420-FYN ProteinP06241 (Uniprot-TrEMBL)
NAD+ MetaboliteCHEBI:15846 (ChEBI)
NF-kB complexComplexR-HSA-194043 (Reactome)
NF-kB complexComplexR-HSA-194047 (Reactome)
NFAT:CaN:CaMComplexR-HSA-2685690 (Reactome)
NFAT:CaN:CaMComplexR-HSA-2685705 (Reactome)
NFKB1(1-433) ProteinP19838 (Uniprot-TrEMBL)
NFKBIA ProteinP25963 (Uniprot-TrEMBL)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PAK dimerComplexR-HSA-2685646 (Reactome)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PDK1:PIP2,PIP3ComplexR-HSA-202311 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PI(3,4)P2 MetaboliteCHEBI:16152 (ChEBI)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3KComplexR-HSA-74693 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (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.
PIP3, PI(3,4)P2ComplexR-ALL-202277 (Reactome)
PKC-theta (open): DAGComplexR-HSA-202187 (Reactome)
PLC gamma1,2ComplexR-HSA-1169089 (Reactome)
PLCG1 ProteinP19174 (Uniprot-TrEMBL)
PLCG2 ProteinP16885 (Uniprot-TrEMBL)
PPP3CA ProteinQ08209 (Uniprot-TrEMBL)
PPP3CB ProteinP16298 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
PRKQC closed conformationProteinQ04759 (Uniprot-TrEMBL)
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)
Phosphorylated NFATC1,2,3ComplexR-HSA-2025924 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-445010 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RASGRP1 ProteinO95267 (Uniprot-TrEMBL)
RASGRP2 ProteinQ7LDG7 (Uniprot-TrEMBL)
RASGRP4 ProteinQ8TDF6 (Uniprot-TrEMBL)
RELA ProteinQ04206 (Uniprot-TrEMBL)
RasGRPs:DAG:Ca2+ComplexR-HSA-2685686 (Reactome)
RasGRPsComplexR-HSA-2685656 (Reactome) Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
SCF-beta-TRCPComplexR-HSA-5607687 (Reactome)
SHC1-2ProteinP29353-2 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYK/FYNComplexR-HSA-2685644 (Reactome)
SYKProteinP43405 (Uniprot-TrEMBL)
TAB1 ProteinQ15750 (Uniprot-TrEMBL)
TAB1:TAB2,TAB3:TAK1ComplexR-HSA-450277 (Reactome)
TAB2 ProteinQ9NYJ8 (Uniprot-TrEMBL)
TAB3 ProteinQ8N5C8 (Uniprot-TrEMBL)
TEC ProteinP42680 (Uniprot-TrEMBL)
TEC,BTK,ITK,(TXK)ComplexR-HSA-2685658 (Reactome)
TRAF6 ProteinQ9Y4K3 (Uniprot-TrEMBL)
TRAF6 oligomer R-HSA-2685708 (Reactome)
TRAF6ProteinQ9Y4K3 (Uniprot-TrEMBL)
TXK ProteinP42681 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D2,UBE2D1,(CDC34)ComplexR-HSA-5607669 (Reactome)
UBE2N ProteinP61088 (Uniprot-TrEMBL)
UBE2V1 ProteinQ13404 (Uniprot-TrEMBL)
Ub-124-UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-124-UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-200-UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-200-UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-276-UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-352-UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-428-UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-48-RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
Ub-48-UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
Ub-48-UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
Ub-48-UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-504-UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-580-UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-656-UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-TRAF6 trimer

bound to CBM

complex		ComplexR-HSA-202456 (Reactome)
Ubc13:UBE2V1ComplexR-HSA-202463 (Reactome)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1,2,3ComplexR-HSA-430172 (Reactome)
VAV2 ProteinP52735 (Uniprot-TrEMBL)
VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
p-10Y-LAT2 ProteinQ9GZY6 (Uniprot-TrEMBL)
p-10Y-LAT2ProteinQ9GZY6 (Uniprot-TrEMBL)
p-10Y-NTAL:p-SHC1:GRB2:SOS:GAB2ComplexR-HSA-2685701 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3KComplexR-HSA-2685700 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2ComplexR-HSA-2685687 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOSComplexR-HSA-2685692 (Reactome)
p-12S-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-13S-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-14S-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-2S-cJUN:p-2S,2T-cFOSComplexR-HSA-450327 (Reactome)
p-2Y-PAKComplexR-HSA-5567354 (Reactome)
p-4Y-PLCG1 ProteinP19174 (Uniprot-TrEMBL)
p-4Y-PLCG2 ProteinP16885 (Uniprot-TrEMBL)
p-5Y-LAT-2 ProteinO43561-2 (Uniprot-TrEMBL)
p-5Y-LAT-2ProteinO43561-2 (Uniprot-TrEMBL)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimerComplexR-HSA-2685694 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTPComplexR-HSA-2685706 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAVComplexR-HSA-2685666 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGComplexR-HSA-2396571 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76ComplexR-HSA-2424464 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3ComplexR-HSA-2685683 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3ComplexR-HSA-2685707 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinasesComplexR-HSA-2685650 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3ComplexR-HSA-2685675 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAVComplexR-HSA-2685668 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGComplexR-HSA-2424460 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1ComplexR-HSA-2424468 (Reactome)
p-5Y-PKC-theta:DAGComplexR-HSA-2685674 (Reactome)
p-6Y-SYK ProteinP43405 (Uniprot-TrEMBL)
p-BCL10 ProteinO95999 (Uniprot-TrEMBL)
p-CARMA1 oligomer R-HSA-2685669 (Reactome)
p-FCERI aggregate R-HSA-2685662 (Reactome)
p-MAP2K4/p-MAP2K7ComplexR-HSA-450299 (Reactome)
p-MAPK8/9/10ComplexR-HSA-450226 (Reactome)
p-MAPK8/9/10ComplexR-HSA-450253 (Reactome)
p-S141,T402-PAK2 ProteinQ13177 (Uniprot-TrEMBL)
p-S144,T423-PAK1 ProteinQ13153 (Uniprot-TrEMBL)
p-S177,S181-IKBKB ProteinO14920 (Uniprot-TrEMBL)
p-S177,S181-IKKB:IKKA:NEMOComplexR-HSA-202513 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOComplexR-HSA-202562 (Reactome)
p-S243-NFATC2 ProteinQ13469 (Uniprot-TrEMBL)
p-S257,T261-MAP2K4 ProteinP45985 (Uniprot-TrEMBL)
p-S257,T261-MAP2K4ProteinP45985 (Uniprot-TrEMBL)
p-S257-NFATC1 ProteinO95644 (Uniprot-TrEMBL)
p-S265-NFATC3 ProteinQ12968 (Uniprot-TrEMBL)
p-S271,T275-MAP2K7 ProteinO14733 (Uniprot-TrEMBL)
p-S271,T275-MAP2K7ProteinO14733 (Uniprot-TrEMBL)
p-S32,36-IkB-alpha:NF-kB complexComplexR-HSA-5607671 (Reactome)
p-S32,S36-NFKBIA ProteinP25963 (Uniprot-TrEMBL)
p-S552,S645-CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
p-S552,S645-CARD11ProteinQ9BXL7 (Uniprot-TrEMBL)
p-S552-CARD11 ProteinQ9BXL7 (Uniprot-TrEMBL)
p-S63,S73-JUN ProteinP05412 (Uniprot-TrEMBL)
p-S63,S73-JUNProteinP05412 (Uniprot-TrEMBL)
p-SHC1:GRB2:SOSComplexR-HSA-2685672 (Reactome)
p-SYK/p-BTKComplexR-HSA-2685648 (Reactome)
p-T,Y MAPK dimersComplexR-HSA-198701 (Reactome)
p-T,Y-MAPK8 ProteinP45983 (Uniprot-TrEMBL)
p-T183,Y185-MAPK9 ProteinP45984 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
p-T221,Y223-MAPK10 ProteinP53779 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOS ProteinP01100 (Uniprot-TrEMBL)
p-T325,T331,S362,S374-FOSProteinP01100 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-LCP2 ProteinQ13094 (Uniprot-TrEMBL)
p-Y1400,Y1412-MAP3K1ProteinQ13233 (Uniprot-TrEMBL)
p-Y172-VAV2 ProteinP52735 (Uniprot-TrEMBL)
p-Y173-VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
p-Y174-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y180,Y512-ITK ProteinQ08881 (Uniprot-TrEMBL)
p-Y206,Y519-TEC ProteinP42680 (Uniprot-TrEMBL)
p-Y223,Y551-BTK ProteinQ06187 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2 ProteinP29353-2 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2ProteinP29353-2 (Uniprot-TrEMBL)
p-Y396-LYN ProteinP07948 (Uniprot-TrEMBL)
p-Y396-LYNProteinP07948 (Uniprot-TrEMBL)
p-Y420-TXK ProteinP42681 (Uniprot-TrEMBL)
p-Y452,Y476,Y584-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y512-ITK ProteinQ08881 (Uniprot-TrEMBL)
p-Y519-TEC ProteinP42680 (Uniprot-TrEMBL)
p-Y551-BTK ProteinQ06187 (Uniprot-TrEMBL)
p-Y90,T219,T538,S676,S695-PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
p-Y90-PKC-theta:DAGComplexR-HSA-202300 (Reactome)
p-Y90-PRKCQ ProteinQ04759 (Uniprot-TrEMBL)
p-Y91,Y420-TXK ProteinP42681 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-5607724 (Reactome)
ADPArrowR-HSA-168136 (Reactome)
ADPArrowR-HSA-168162 (Reactome)
ADPArrowR-HSA-202541 (Reactome)
ADPArrowR-HSA-2454208 (Reactome)
ADPArrowR-HSA-2454239 (Reactome)
ADPArrowR-HSA-2730833 (Reactome)
ADPArrowR-HSA-2730835 (Reactome)
ADPArrowR-HSA-2730841 (Reactome)
ADPArrowR-HSA-2730843 (Reactome)
ADPArrowR-HSA-2730851 (Reactome)
ADPArrowR-HSA-2730856 (Reactome)
ADPArrowR-HSA-2730858 (Reactome)
ADPArrowR-HSA-2730860 (Reactome)
ADPArrowR-HSA-2730862 (Reactome)
ADPArrowR-HSA-2730863 (Reactome)
ADPArrowR-HSA-2730868 (Reactome)
ADPArrowR-HSA-2730870 (Reactome)
ADPArrowR-HSA-2730876 (Reactome)
ADPArrowR-HSA-2730882 (Reactome)
ADPArrowR-HSA-2730884 (Reactome)
ADPArrowR-HSA-2730886 (Reactome)
ADPArrowR-HSA-2730887 (Reactome)
ADPArrowR-HSA-2730888 (Reactome)
ADPArrowR-HSA-2730896 (Reactome)
ADPArrowR-HSA-2730900 (Reactome)
ADPArrowR-HSA-450325 (Reactome)
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramerTBarR-HSA-169683 (Reactome)
AMPArrowR-HSA-2730904 (Reactome)
ATPR-HSA-168136 (Reactome)
ATPR-HSA-168162 (Reactome)
ATPR-HSA-202541 (Reactome)
ATPR-HSA-2454208 (Reactome)
ATPR-HSA-2454239 (Reactome)
ATPR-HSA-2730833 (Reactome)
ATPR-HSA-2730835 (Reactome)
ATPR-HSA-2730841 (Reactome)
ATPR-HSA-2730843 (Reactome)
ATPR-HSA-2730851 (Reactome)
ATPR-HSA-2730856 (Reactome)
ATPR-HSA-2730858 (Reactome)
ATPR-HSA-2730860 (Reactome)
ATPR-HSA-2730862 (Reactome)
ATPR-HSA-2730863 (Reactome)
ATPR-HSA-2730868 (Reactome)
ATPR-HSA-2730870 (Reactome)
ATPR-HSA-2730876 (Reactome)
ATPR-HSA-2730882 (Reactome)
ATPR-HSA-2730884 (Reactome)
ATPR-HSA-2730886 (Reactome)
ATPR-HSA-2730887 (Reactome)
ATPR-HSA-2730888 (Reactome)
ATPR-HSA-2730896 (Reactome)
ATPR-HSA-2730900 (Reactome)
ATPR-HSA-2730904 (Reactome)
ATPR-HSA-450325 (Reactome)
Allergin:p-LYN:p-FCERI:IgE aggregateArrowR-HSA-2454208 (Reactome)
Allergin:p-LYN:p-FCERI:IgE aggregateR-HSA-2454240 (Reactome)
Allergin:p-LYN:p-FCERI:IgE aggregatemim-catalysisR-HSA-2730882 (Reactome)
AllerginR-HSA-2454192 (Reactome)
BCL10:MALT1R-HSA-2730836 (Reactome)
BCL10R-HSA-2730899 (Reactome)
CALM1:4xCa2+ArrowR-HSA-74448 (Reactome)
CALM1:4xCa2+R-HSA-2730872 (Reactome)
CALM1R-HSA-74448 (Reactome)
CARD11R-HSA-2730863 (Reactome)
Ca2+ArrowR-HSA-169683 (Reactome)
Ca2+R-HSA-169683 (Reactome)
Ca2+R-HSA-2730871 (Reactome)
Ca2+R-HSA-2730872 (Reactome)
Ca2+R-HSA-74448 (Reactome)
Calcineurin (CaN)R-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)ArrowR-HSA-2730872 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)R-HSA-2730849 (Reactome)
Calcineurin:Calmodulin (CaN:CaM)mim-catalysisR-HSA-2730849 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:SYKArrowR-HSA-2454240 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:SYKR-HSA-2454239 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:SYKmim-catalysisR-HSA-2454239 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKArrowR-HSA-2454239 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKmim-catalysisR-HSA-2730833 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKmim-catalysisR-HSA-2730843 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKmim-catalysisR-HSA-2730851 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKmim-catalysisR-HSA-2730884 (Reactome)
Clustered p:LYN:p-FCERI:IgE:allergin:p-6Y-SYKmim-catalysisR-HSA-2730886 (Reactome)
DAG:p-5Y-PKC-theta:CBM complexArrowR-HSA-2730836 (Reactome)
DAG:p-5Y-PKC-theta:CBM complexR-HSA-2730899 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomerArrowR-HSA-2730903 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomerR-HSA-2730904 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6 oligomermim-catalysisR-HSA-2730904 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6ArrowR-HSA-2730864 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:TRAF6R-HSA-2730903 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3ArrowR-HSA-2730861 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3R-HSA-2730900 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:TAK1:TAB1:TAB2/3mim-catalysisR-HSA-2730900 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:activated TAK1 complexArrowR-HSA-2730900 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6:activated TAK1 complexmim-catalysisR-HSA-2730876 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6ArrowR-HSA-2730904 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomer:oligo-K63-poly Ub-TRAF6R-HSA-2730861 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomerArrowR-HSA-2730899 (Reactome)
DAG:p-5Y-PKC-theta:CBM oligomerR-HSA-2730864 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomerArrowR-HSA-2730902 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1 oligomerR-HSA-2730836 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1ArrowR-HSA-2730863 (Reactome)
DAG:p-5Y-PKC-theta:p-S552,S645-CARMA1R-HSA-2730902 (Reactome)
DAGsArrowR-HSA-2730847 (Reactome)
DAGsR-HSA-2730871 (Reactome)
DAGsR-HSA-2730875 (Reactome)
FCERI:IgE:allergin aggregateArrowR-HSA-2454192 (Reactome)
FCERI:IgE:allergin aggregateR-HSA-2454208 (Reactome)
FCERI:IgER-HSA-2454192 (Reactome)
FOSR-HSA-450325 (Reactome)
GAB2R-HSA-2730848 (Reactome)
GADS:SLP76R-HSA-2396561 (Reactome)
GDPArrowR-HSA-2424477 (Reactome)
GDPArrowR-HSA-2730840 (Reactome)
GRB2-1:SOS1R-HSA-2730844 (Reactome)
GTPR-HSA-2424477 (Reactome)
GTPR-HSA-2730840 (Reactome)
H2OR-HSA-2730847 (Reactome)
H2OR-HSA-2730849 (Reactome)
I(1,4,5)P3ArrowR-HSA-169683 (Reactome)
I(1,4,5)P3ArrowR-HSA-2730847 (Reactome)
I(1,4,5)P3R-HSA-169680 (Reactome)
IKKA:IKBKB:IKBKGR-HSA-2730876 (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-169683 (Reactome)
IkB(alpha):NF-kB complexR-HSA-202541 (Reactome)
JUNR-HSA-168136 (Reactome)
K48-UbR-HSA-5607728 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexArrowR-HSA-5607728 (Reactome)
K48PolyUb-K21,22-p-S32,36-IkBA:NF-kB complexR-HSA-5607724 (Reactome)
K63polyUbR-HSA-202534 (Reactome)
K63polyUbR-HSA-2730904 (Reactome)
LAT-2R-HSA-2730843 (Reactome)
LAT2R-HSA-2730884 (Reactome)
LYNR-HSA-2730862 (Reactome)
LYNmim-catalysisR-HSA-2730862 (Reactome)
MALT1R-HSA-2730899 (Reactome)
MAP2K4R-HSA-2730896 (Reactome)
MAP2K7R-HSA-2730868 (Reactome)
MAP3K1R-HSA-2730887 (Reactome)
MAP3K1mim-catalysisR-HSA-2730887 (Reactome)
MAPK8/9/10R-HSA-168162 (Reactome)
NF-kB complexArrowR-HSA-2730894 (Reactome)
NF-kB complexArrowR-HSA-5607724 (Reactome)
NF-kB complexR-HSA-2730894 (Reactome)
NFAT:CaN:CaMArrowR-HSA-2730849 (Reactome)
NFAT:CaN:CaMArrowR-HSA-2730867 (Reactome)
NFAT:CaN:CaMR-HSA-2730867 (Reactome)
PAK dimerR-HSA-2730889 (Reactome)
PDK1:PIP2,PIP3ArrowR-HSA-202164 (Reactome)
PDPK1R-HSA-202164 (Reactome)
PI(3,4,5)P3ArrowR-HSA-2730870 (Reactome)
PI(3,4,5)P3R-HSA-2730841 (Reactome)
PI(3,4,5)P3R-HSA-2730848 (Reactome)
PI(3,4,5)P3R-HSA-2730885 (Reactome)
PI(4,5)P2R-HSA-2730847 (Reactome)
PI(4,5)P2R-HSA-2730870 (Reactome)
PI3KR-HSA-2730842 (Reactome)
PIP3, PI(3,4)P2R-HSA-202164 (Reactome)
PKC-theta (open): DAGArrowR-HSA-2730875 (Reactome)
PKC-theta (open): DAGR-HSA-2730882 (Reactome)
PLC gamma1,2R-HSA-2396606 (Reactome)
PPiArrowR-HSA-2730904 (Reactome)
PRKQC closed conformationR-HSA-2730875 (Reactome)
Phosphorylated NFATC1,2,3R-HSA-2730849 (Reactome)
PiArrowR-HSA-2730849 (Reactome)
R-HSA-168136 (Reactome) JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.
R-HSA-168162 (Reactome) Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK.

JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183).

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-202164 (Reactome) PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck & Alessi 2000).
R-HSA-202534 (Reactome) During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).
R-HSA-202541 (Reactome) NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 2000)
R-HSA-2396561 (Reactome) Gads/GRAP2 (GRB2-related adapter protein 2) is member of the GRB2 adaptor family with a central SH2 domain and linker region flanked by amino- and carboxy-terminal SH3 domains. SLP-76 associates constitutively via its central 20-amino acid proline-rich domain with the C-terminal SH3 domain of Gads, which recruits it to LAT following receptor stimulation. Upon LAT phosphorylation, Gads:SLP-76 complex principally binds to phosphorylated LAT tyrosine 191, with a reduced amount of binding to phosphorylated tyrosine 171 and no interaction with phosphorylated tyrosines 132 or 226 (Houtman et al. 2004, Zhu et al. 2003). Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways (Liu et al. 1999). The LAT-Gads-SLP-76 complex creates a platform for the recruitment of multiple signaling molecules, including PLCgamma1, GRB2, NCK, Rho GEFs, VAV and the Tec-family kinases ITK and BTK (Liu et al. 1999 & 2001, Asada et al. 1999, Yablonski et al. 2001).
R-HSA-2396599 (Reactome) GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). Following phosphorylation of LAT, the GRB2:SOS complex binds to the phosphorylated tyrosines and is thereby translocated to the inner face of the plasma membrane where inactive RAS:GDP resides. The three distal tyrosines, Y171, Y191 and Y226 of LAT are responsible for GRB2 association (Balagopalan et al. 2010, Zhang et al. 2000).
R-HSA-2396606 (Reactome) The phospholipase PLC-gamma is an important mediator of TCR, FCERI and DAP12 signal transduction. PLC-gamma hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) and in-turn promotes the Ca+2 influx and activation of NFAT. Activation of PLC-gamma1 entails the binding of PLC-gamma1 to both LAT and SLP-76 adapter proteins. The amino-terminal SH2 domain of PLC-gamma1 was shown to preferentially bind phosphorylated LAT Y132 with high affinity and no detectable binding to phosphorylated tyrosines 171, 191, and 226. PLC-gamma1 was also shown to bind the adapter protein SLP-76 indirectly through GADS, which is bound to LAT at Y171 and Y191. SH3 domain of PLC-gamma1 associates with the proline-rich region of SLP-76 (Yablonski et al. 2001). PLC-gamma1 associates with Gads/SLP-76 complex before binding to p-Y132 of LAT (Houtman et al. 2005). PLC-gamma1 association with LAT is stabilized by Gads/SLP-76 bound to LAT (Zhu et al.2003). Association of PLC-gamma to LAT and SLP-76 couples it to the kinases (Syk and Tec family kinase) required for tyrosine phosphorylation and activation of PLC-gamma.
Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms, which are phosphorylated by BTK/ITK and/or SYK. FCERI-dependent Ca2+ release requires the recruitment of PLC-gamma by SLP-76 and LAT. In mast cells, increased intracellular calcium triggers rapid release of preformed mediators, through a process of vesicle exocytosis, known as degranulation.
Recruitment and activation of phospholipase C gamma (PLC-gamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLC-gamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLC-gamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010).
R-HSA-2424477 (Reactome) GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation.
R-HSA-2454192 (Reactome) FCERI is primarily expressed on mast cells and basophils as a tetrameric complex comprising an IgE-binding alpha subunit, a signal amplifying membrane-tetraspanning beta subunit, and a disulfide-linked gamma chain dimer that provides the receptor its signaling competence (Blank & Rivera 2004). In the absence of an antigen or allergen, FCERI receptor binds to monomeric IgE antibodies, and thus the receptor adopts the antigenic specificity of the prevalent IgE repertoire (Garman et al. 2000). Mast cell activation is initiated when multivalent antigen crosslinks the IgE bound to the high-affinity FCERI, thereby aggregating FCERI (Siraganian 2003). Antigen driven aggregation of FCERI then elicits intracellular signals that result in mast cell exocytosis.
R-HSA-2454208 (Reactome) Upon FCGRI-IgE aggregation, LYN kinase phosphorylates the tyrosine residues within the ITAM (immunoreceptor tyrosine-based activation motifs) of both the beta and gamma subunits. The detailed mechanism of the initial engagement of LYN kinase and FCERI is incompletely understood, but two different models have been proposed. One model postulates that a small fraction of LYN is constitutively bound to beta subunit of FCERI prior to activation. Aggregation of FCERI facilitates the transphosphorylation of one FCERI by LYN bound to a juxtaposed receptor (Vonakis et al. 1997, Draber & Draberova 2002). Alternative model postulates that LYN is observed in lipid rafts enriched in glycosphingolipids, cholesterol, and glycosylphosphatidylinositol-anchored proteins and upon aggregation, FCERI rapidly translocates into lipid rafts, where it is phosphorylated by LYN kinase. Either the association of LYN or FCERI or both with lipid rafts is important for initiating this phosphorylation process (Young et al. 2003, Kovarova et al. 2002, Draber & Draberova 2002).
Beta subunit ITAM differs from canonical ITAMs in two ways; the spacing between the two canonical tyrosines harbours a third tyrosine, and it is one amino acid shorter than in canonical ITAMs, thus making it unfit to bind and recruit Syk. Among the three tyrosine residues (Y219, Y225 and Y229), Y219 may play a predominant role in beta chain function and LYN recruitment. Mutation of this tyrosine would decrease substantially LYN association and subsequent phosphorylation of Y225 and Y229. This would result in decreased gamma phosphorylation and decreased SYK recruitment and activation (On et al. 2004).
R-HSA-2454239 (Reactome) Multiple sites of phosphorylation are known to exist in SYK, which both regulate its activity and also serve as docking sites for other proteins. Some of these sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, and Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997). Phosphorylation of these tyrosine residues disrupts autoinhibitory interactions and results in kinase activation even in the absence of phosphorylated ITAM tyrosines (Tsang et al. 2008). SYK is primarily phosphorylated by Src family kinases and this acts as an initiating trigger by generating few molecules of activated SYK which are then involved in major SYK autophosphorylation (Hillal et al. 1997).
R-HSA-2454240 (Reactome) Tyrosine phosphorylated ITAM in FCERI gamma subunit serves as docking site for SYK (spleen tyrosine kinases), whereas the beta-subunit ITAM has an extra tyrosine and is shorter than canonical ITAM which makes it unfit to bind SYK. Association of SYK to FCERI gamma-subunit disrupts the COOH-terminal-SH2 interdomain interaction of SYK causing a conformational change opening the molecule leading to its activation (Siraganian et al. 2010, de Castro et al. 2010).
R-HSA-2730833 (Reactome) BTK/ITK are activated in a two step model. In the first step they are recruited to the membrane by binding to PIP3 or, alternatively with other binding partners like SLP-76. Once at the membrane SYK or Src-kinases in the vicinity phosphorylates Y551 (Y512 in ITK) in the activation loop of the catalytic domain of BTK to fully activate it (Rawlings et al. 1996, Park et al. 1996, Kawakami et al. 1994).
R-HSA-2730835 (Reactome) T219, T538 at the activation loop, S676 at the turn motif and S695 at the hydrophobic motif are autophosphorylated in cis-maanner. Posphorylation of T538 is critical for kinase activation and it stabilises the open active conformation. Some studies suggest the involvement of PDK1 (3-phosphoinositide-dependent protein kinase 1) and GLK kinases in the phosphorylation T538.
R-HSA-2730836 (Reactome) Phosphorylation of CARMA1 causes conformational change such that its CARD motif is exposed and is free to interact with BCL10 CARD motif. BCL10 constitutively associated with MALT1 and exists as a preformed complex in the cytoplasm. BCL10 and MALT1 have been identified as key positive regulators of FCERI-dependent NF-kB activation (Klemm et al. 2006). The resulting CARMA1-BCL10-MALT1 (CBM) complex may be stabilized by interactions between the CARMA1 coiled coil (CC) domain and a C-terminal MALT1 region that lacks the DD and first two Ig domains (Thome et al. 2010, Che et al. 2004). The CBM complex transmits activating signals that ultimately result in ubiquitination (Ub) and degradation of the NF-kB inhibitor, IkBa.
R-HSA-2730837 (Reactome) Upon phosphorylation NATL/LAT2 recruits GRB2:SOS complex into the receptor-signaling complex. Residues Y95, Y118, Y136, Y193, Y233 are the putative GRB2-binding sites on NTAL (Iwaki et al. 2007).
R-HSA-2730840 (Reactome) Rac1 exists in inactive state in the cytosol until the reception of extracellular signals by the cell. To be functional Rac1 is rapidly targeted to the plasma membrane upon cell stimulation. The main factors involved in this mobilisation are the Rac GEFs like VAV and phospholipids (PtdIns(4,5)P2, PtdIns(3,4,5) P3) and lipid rafts at the plasma membrane. VAV catalyses the disassociation of GDP from Rac1 by modifying the nucleotide-binding site such that GDP is released and subsequently replaced. The incoming GTP occupies the nucleotide binding site and finally displaces VAV from Rac1 (Bos et al. 2007, Bustelo et al. 2012).
R-HSA-2730841 (Reactome) Phosphorylation of VAV stimulates its GEF activity for RAC1, and thus it plays an important role in linking FCERI to the RAC1-JNK pathway. VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV is phosphorylated on tyrosine residue (Y174 in VAV1/172 in VAV2/173 in VAV3) in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV is involved in the activation of RAC1, PAK1, MEK and ERK and cytokine production.
R-HSA-2730842 (Reactome) Phosphorylated Y452, Y476, and Y584 of GAB2 binds p85 regulatory subunit of PI3K kinase, resulting in activation of PI3K pathway. PI3K is required for mast cell degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity (Nishida et al. 2011). Activated PI3K generates second messenger PtdInsP3 (PIP3) at the inner membrane, which provides docking sites for pleckstrin homology (PH) domains of PDK1, AKT and BTK. Activated AKT controls major downstream targets like mTORC1, FOXO3 and GSK3beta pathways that regulate mast cell growth, homeostasis, and cytokine production. BTK triggers PLCgamma2 activation, thereby inducing activation of the transcription factor NFAT and NF-kB.
R-HSA-2730843 (Reactome) LAT is palmitoylated and membrane-associated adaptor protein. It rapidly becomes tyrosine-phosphorylated upon receptor engagement. LAT has nine conserved tyrosine residues of which five have been shown to undergo phosphorylation (Y127, Y132, Y171, Y191 and Y226). Src family kinases, SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues (Jiang & Cheng 2007, Paz et al. 2001). Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domain proteins PLC-gamma1, GRB2 and GADS, which indirectly bind SOS, VAV, SLP-76 and ITK (Wange 2000).
R-HSA-2730844 (Reactome) GRB2 is an adapter protein that contains a central SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). GRB2-SOS complex binds to phosphotyrosine Y239 and Y317 of SHC1. SHC1 associates with the tyrosine-phosphorylated ITAMs of the FCERI beta-chain and can recruit SOS to membrane. SHC1 and SOS have also been described to associate with LAT via GRB2. Shc binding to Phospho-ITAMs (in vitro binding to phospho peptides) has never been linked to any biological function (activation) and is probably not relevant in a physiological setting.
R-HSA-2730847 (Reactome) Phosphoinositol 4,5-bisphosphate (PIP2) is cleaved in to two most important second messengers diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC). DAG remains within the membrane and activates protein kinase C (PKC) while IP3 leaves the cell membrane and binds to IP3 receptor that releases Ca2+ from endoplasmic reticulum (ER).
R-HSA-2730848 (Reactome) NTAL cooperates with LAT in mast cells to activate PI3K pathway and cytokine production through Grb2-associated binding protein 2 (GAB2) (Gonzalez-Espinosa et al. 2003). FCERI aggregation induced translocation of a significant fraction of GAB2 from the cytosol to the plasma membrane by binding GRB2. Two of the proline-rich motifs in GAB2 are binding sites for the SH3 of GRB2. GAB2 is also recruited to plasma membrane by binding to phosphatidylinositol-3,4,5-trisphosphate (PIP3) with its plecstrin homology (PH) domain. GAB2 can be recruited to FCERI indirectly through GRB2 bound SHC1. SHC1 is recruited to the FCERI beta chain through its SH2 domain and becomes tyrosyl-phosphorylated. Phosphorylated SHC provides a docking site for the GRB2 and this in turn recruits GAB2 (Yu et al. 2006). GAB2 and PI3K are required for FCERI-induced granule translocation.
R-HSA-2730849 (Reactome) Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003).
R-HSA-2730851 (Reactome) SLP-76 lacks intrinsic catalytic activity and acts as a scaffold, recruiting other proteins for correct localization during molecular signal transduction (Bogin et al. 2007). Activation of FCERI leads to tyrosine phosphorylation of SLP-76 (Gross et al. 1999). SLP-76 has three potential tyrosine phosphorylation sites within its amino terminus region: Y113, Y128, and Y145. Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996).
R-HSA-2730856 (Reactome) Upon dimer disassociation PAK1 autophosphorylates in both cis- and trans- manner. Serine 144 (S144) in the GTPase-binding domain and threonine 423 (T423) in the activation loop are the target sites for autophosphorylation (Parrini et al. 2002).
R-HSA-2730858 (Reactome) After initial phosphorylation by SFK's, subsequently Y223 (Y180 in ITK and Y206 in TEC) in the SH3 domain of BTK is autophosphorylated, which may prevent inhibitory intramolecular interactions (Nore et al. 2003, Joseph et al. 2007, Park et al. 1996)
R-HSA-2730860 (Reactome) GAB2 have multiple tyrosyl phosphorylation sites that are phosphorylated up on activation of FCERI. SYK is the major tyrosine kinase involved in GAB2 phosphorylation. FYN is also shown to contribute to GAB2 tyrosyl phosphorylation but it is not clear whether GAB2 is a direct substrate of FYN (Yu et al. 2006, Parravicini et al. 2002). GAB2 tyrosines (Y452, Y476 and Y584) in the YXXM motif can be the target phosphorylation sites for SYK/FYN kinases (Chan et al. 2010, Harir et al. 2007).
R-HSA-2730861 (Reactome) K-63 linked polyubiquitin (pUb) chain on TRAF6 provides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). TAK1-binding protein 1 (TAB1), TAB2 and TAB3 constitutively bound to TAK1. TAB1 acts as the activation subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, act as a adaptors of TAK1 that facilitate the assembly of TAK1 complex to TRAF6. The highly conserved C-terminal zinc finger domain of TAB2 and TAB3 binds preferentially to the K-63-linked polyubiquitin chains on TRAF6 (Broglie et al. 2009, Besse et al. 2007).
R-HSA-2730862 (Reactome) LYN localized in lipid rafts undergoes an intermolecular autophosphorylation at tyrosine 396. This residue is present in the activation loop, and its phosphorylation promotes LYN kinase activity.
R-HSA-2730863 (Reactome) CARMA1 (CARD11/Caspase recruitment domain-containing protein 11), BCL10 (B-cell lymphoma/leukemia 10) and MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1)/paracaspase have been identified as signaling components that act downstream of PKC-theta. CARMA1 is a scaffold protein and recruits BCL10, MALT1, PKC and TRAF6 to form a multi protein complex. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. Upon stimulation S552 and S645 linker residues are phosphorylated by PKC-theta and this may weaken this interaction, inducing an open conformation of CARMA1. Further phosphorylation studies have revealed other phosphorylation sites (S109, S551 and S555) that may also promote activation of CARMA1. Serene/threonine kinases PKC-beta, IKKbeta, HPK1 and CaMKII are involved in triggering CARMA1 activation (Thome et al. 2010, Rueda & Thome 2005). (only phosphorylated S552 and S645 are represented in this reaction)
R-HSA-2730864 (Reactome) TRAF6 is a ubiquitin ligase that plays a central role in the IKK-dependent canonical NF-kB pathway. It is recruited to the CBM complex by binding to MALT1. The MALT1 C-terminal Ig domain and extension contain two binding motifs for TRAF6 (Noels et al 2007). After oligomerzation TRAF6, together with Ubc13/Uev1A, activates TAK1 and IKK. It also acts as an E3 ligase for MALT1 and mediates lysine 63-linked ubiquitination (Oeckinghaus et al. 2007).
R-HSA-2730867 (Reactome) Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2).
R-HSA-2730868 (Reactome) MKK7 is activated by MEKK1 and the residues serine 271 and threonine 275 are the potential phosphorylation sites that are crucial for its kinase activity (phosphorylation sites are based on sequence alignment with MAP kinase kinase family members).
R-HSA-2730870 (Reactome) PI3K catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and AKT.
R-HSA-2730871 (Reactome) Ras guanyl nucleotide-releasing proteins (RasGRPs) are guanyl nucleotide exchange factors (GEFs) that activate Ras ultimately leading to MAPK activation. RasGRPs have a catalytic domain composed of Ras exchange motif (REM) and a CDC25 domain, an atypical pair of EF hands that bind calcium and a DAG-binding C1 domain. After PIP2 hydrolysis, RasGRPs are recruited to the plasma membrane by binding to DAG and calcium (Stone 2011, Liu et al. 2007). Upon T-cell activation RasGRP1 specifically interacts with and activates Ras on Golgi instead of the plasma membrane (Bivona et al. 2003). It remains to be determined whether activation of N-Ras by RasGRP1 in mast cells occurs in the Golgi or the plasma membrane (Liu et al. 2007). RasGRP4 is mast cell specific and is involved in the controls Ras activation.
R-HSA-2730872 (Reactome) Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000).
R-HSA-2730875 (Reactome) DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell degranulation and cytokine production (Wu 2011). MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007).
R-HSA-2730876 (Reactome) In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex.
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
R-HSA-2730882 (Reactome) Raft localized PKC-theta is phosphorylated and is activated. Phosphorylation of both tyrosine and serine-threonine residues is important in the regulation of PKC function. Six phosphorylation sites have been identified on PKC-theta: Y90, T219, T538, S676, S685, and S695. Phosphorylation of Y90 positively regulates NF-AT and NF-kB activation in T-cells. In mast cells Src family members Src and LYN have been shown to be involved in phosphorylating Y90 (Wang et al. 2012, Liu et al. 2001).
R-HSA-2730884 (Reactome) NTAL and LAT play complementary roles in the positive regulation of FCERI-mediated degranulation. Upon FCERI aggregation NTAL is phosphorylated by LYN, SYK and KIT on different tyrosines. Phosphorylated NTAL likely contributes to the activation of mast cells by providing docking sites for the recruitment of critical signaling molecules into the lipid raft. There are about ten tyrosines in LAT2 of which five tyrosines principally phosphorylated by SYK are recognised as putative GRB2-binding sites, being part of a YXN motif, whereas LYN and KIT phosphorylate both tyrosines contained in the YXN motifs as well as tyrosines outside of the YXN motifs (Iwaki et al. 2008).
R-HSA-2730885 (Reactome) Mast cells express four out of five Tec family members (i.e. BTK, ITK, RLK and TEC) and are activated upon cross-linking of FCERI. They are recruited to the membrane via the interaction of their PH domain with PtdIns(3,4,5)P3 phosphate and their SH2 domain with Y145 of SLP-76 (Kettner et al. 2003). BTK is more important for early response such as phosphorylation of PLC-gamma2 and Ca2+ mobilization, whereas ITK regulates the late responses such as changes in gene expression and cytokine secretion. BTK deficient mice have mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FCERI cross-linking (Hata et al. 1998). ITK deficient mice have been reported to have reduced MC degranulation and responses to allergic asthma (Forssell et al. 2005). However, Bone marrow derived mast cells (BMMC) derived from ITK deficient mice display a normal degranulation response but secrete elevated level of cytokines (TNFa and IL-13) (Iyer & August 2008). TEC kinase is also one of the crucial regulators of murine mast cell function. TEC is phosphorylated and activated upon FCERI stimulation. TEC deficient bone marrow derived mast cells did not show any in vitro or in vivo defects in histamine release. However, the generation of the leukotriene LTC4 was severely impaired in the absence of TEC (Schmidt et al. 2009).
R-HSA-2730886 (Reactome) SHC is an adapter protein that has been implicated in Ras activation. Mast cells express two isoforms of 46 and 52 kDa. Both isoforms of SHC have two domains, an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal SH2 domain that allows Shc to bind to proteins containing phosphorylated tyrosine residues. Following receptor stimulation, SHC is phosphorylated by Src kinases Syk on Y239, Y240 and Y317 (p56 isoform). Both phosphotyrosines Y239 and Y317 creates the binding site for the SH2 domain of GRB2.
R-HSA-2730887 (Reactome) FCERI aggregation has been shown to activate JNK as well as protein kinases upstream of JNK, such as MEKK1 (Mitogen-activated protein kinase/ERK Kinase Kinase-1) and JNK kinase (JNKK). PAK has been shown to be the upstream kinase involved in the activation of MEKK1, however no direct phosphorylation of MEKK1 by PAK is observed. Two threonine residues at positions 1400 and 1412 (analogous to 1381 and 1393 in mouse) in the activation loop of MEKK1 between the kinase subdomains VII and VIII are essential for its catalytic activity. The catalytic domain of MEKK1 is able to autophosphorylate these residues, enhancing its own activity.
R-HSA-2730888 (Reactome) Tyrosine phosphorylation of PLC-gamma enhances its catalytic activity. BTK and SYK are involved in the phosphorylation of PLC-gamma (PLCG). Phosphorylation of tyrosine residues 753, 759, 1197, and 1217 in PLCG2 and 771, 783, and 1254 in PLCG1 have been identified as BTK/SYK-dependent phosphorylation sites.
R-HSA-2730889 (Reactome) PAK1 kinase is a member of serine/threonine protein kinase family and is widely believed as mediator between Cdc42 and Rac1 and the JNK signal transduction pathway. PAK1 is involved in regulating FCERI mediated mast cell degranulation via effects on calcium mobilisation and cytoskeletal changes (Allen et al. 2009). The conventional PAK family contains a N-terminal conserved Cdc42/Rac-interacting binding domain (CRIB) that overlaps a kinase inhibitory (KI) domain and a C-terminal catalytic domain. PAK1 molecules form trans-inhibited homodimers in which the N-terminal kinase inhibitory (KI) domain of one PAK1 molecule in the dimer binds and inhibits the C-terminal catalytic domain of the other. Isoprenylated Rac1/Cdc42-GTP localized to the membrane recruits PAK1 by binding to the N-terminal CRIB domain. Binding of activated Cdc42/Rac1, breaks the PAK1-dimer and removes the trans-inhibition and stimulates serine/threonine kinase activity of that allows autophosphorylation (Lu & Mayer 1999, Parrini et all. 2009, Zhao et al. 2005).
R-HSA-2730892 (Reactome) VAV an activator of RAC-GTPases, is redistributed to plasma membrane and is phosphorylated following engagement of FCERI. Phosphorylated SLP-76 tyrosines Y113 and Y128 (112Y and 128Y in mouse) provide binding sites for the SH2 domains of VAV. The binding of VAV to these phosphotyrosine residues may link SLP-76 to the Jun amino-terminal kinase (JNK) pathway and the actin cytoskeleton (Kettner et al. 2003).
In addition to its known role as guanine nucleotide exchange factor (GEF), VAV also modulates cytokine production in mast cells. VAV1-deficient bone marrow-derived mast cells exhibited reduced degranulation and cytokine production and calcium release in addition of reduced activation of c-Jun NH2-terminal kinase 1 (JNK1), although tyrosine phosphorylation of FCERI, SYK and LAT was normal (Manetz et al. 2001, Arudchandran et al. 2000, Song et al. 1999).
R-HSA-2730894 (Reactome) The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) then moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
R-HSA-2730896 (Reactome) Activated MEKK1 then phosphorylates and activates SAPK/Erk kinase (SEK1), also known as MKK4 or Jun kinase kinase (JNKK) on serine and threonine residues at positions 257 and 261, respectively.
R-HSA-2730899 (Reactome) BCL10 and MALT1 proteins form high molecular weight oligomers and only these oligomeric forms can activate IKK in vitro (Sun et al. 2004). BCL10 proteins form homo-oligomers through CARD-CARD interactions whereas in MALT1 the tandem Ig-like domains naturally form oligomers with a tendency towards dimers and tetramers (Dong et al. 2006, Quiu & Dhe-Paganon 2011). These CBM oligomers provides the molecular platform, which can facilitate dimerization or serve as scaffolds on which proteases and kinases involved in NF-kB activation are assembled and activated.
R-HSA-2730900 (Reactome) Binding of TAB2 and TAB3 to K63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Phosphorylation of TAK1 within the activation loop of the kinase is absolutely required for TAK1 activity. TAB1 is known to augment TAK1 catalytic activity by mediating spontaneous oligomerization and induces autophosphorylation of TAK1 (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Some biochemical studies revealed that free K63 polyubiquitin chains, which are not conjugated to any cellular protein, can directly activate the TAK1 kinase complex (Xia et al. 2009).
R-HSA-2730902 (Reactome) CARMA1 phosphorylation initiates its oligomerization and the coiled-coil (CC) domain of CARMA1 is hypothesized to mediate this clustering (Tanner et al. 2007).
R-HSA-2730903 (Reactome) BCL10-MALT1 oligomers bind to TRAF6 and this inturn promotes the oligomerization of TRAF6 and activates its E3 ligase activity (Sun et al. 2004).
R-HSA-2730904 (Reactome) TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
R-HSA-450292 (Reactome) The bZIP domains of Jun and Fos form an X-shaped -helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).
R-HSA-450325 (Reactome) The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity.

On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.

Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.

R-HSA-450348 (Reactome) c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors.
R-HSA-5607724 (Reactome) Following ubiquitination Ikappa B-alpha (IKBA) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).
R-HSA-5607728 (Reactome) Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).
R-HSA-74448 (Reactome) Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions.
RAC1:GDPR-HSA-2730840 (Reactome)
RasGRPs:DAG:Ca2+ArrowR-HSA-2730871 (Reactome)
RasGRPsR-HSA-2730871 (Reactome)
SCF-beta-TRCPArrowR-HSA-5607728 (Reactome)
SCF-beta-TRCPR-HSA-5607728 (Reactome)
SCF-beta-TRCPmim-catalysisR-HSA-5607728 (Reactome)
SHC1-2R-HSA-2730886 (Reactome)
SYK/FYNmim-catalysisR-HSA-2730860 (Reactome)
SYKR-HSA-2454240 (Reactome)
TAB1:TAB2,TAB3:TAK1R-HSA-2730861 (Reactome)
TEC,BTK,ITK,(TXK)R-HSA-2730885 (Reactome)
TRAF6R-HSA-2730864 (Reactome)
TRAF6R-HSA-2730903 (Reactome)
UBE2D2,UBE2D1,(CDC34)ArrowR-HSA-5607728 (Reactome)
UBE2D2,UBE2D1,(CDC34)R-HSA-5607728 (Reactome)
Ub-TRAF6 trimer

bound to CBM

complex		mim-catalysisR-HSA-202534 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-202534 (Reactome)
Ubc13:UBE2V1ArrowR-HSA-2730904 (Reactome)
Ubc13:UBE2V1R-HSA-202534 (Reactome)
Ubc13:UBE2V1R-HSA-2730904 (Reactome)
VAV1,2,3R-HSA-2730892 (Reactome)
p-10Y-LAT2ArrowR-HSA-2730884 (Reactome)
p-10Y-LAT2R-HSA-2730837 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:GAB2ArrowR-HSA-2730848 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:GAB2R-HSA-2730860 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3KArrowR-HSA-2730842 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2:PI3Kmim-catalysisR-HSA-2730870 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2ArrowR-HSA-2730860 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOS:p-3Y-GAB2R-HSA-2730842 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOSArrowR-HSA-2730837 (Reactome)
p-10Y-NTAL:p-SHC1:GRB2:SOSR-HSA-2730848 (Reactome)
p-2S-cJUN:p-2S,2T-cFOSArrowR-HSA-450292 (Reactome)
p-2Y-PAKArrowR-HSA-2730856 (Reactome)
p-2Y-PAKArrowR-HSA-2730887 (Reactome)
p-5Y-LAT-2ArrowR-HSA-2730843 (Reactome)
p-5Y-LAT-2R-HSA-2396599 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimerArrowR-HSA-2730889 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimerR-HSA-2730856 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTP:PAK dimermim-catalysisR-HSA-2730856 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTPArrowR-HSA-2730840 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTPArrowR-HSA-2730856 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAV:RAC1-GTPR-HSA-2730889 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAVArrowR-HSA-2730841 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAVR-HSA-2730840 (Reactome)
p-5Y-LAT:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:PIP3:p-VAVmim-catalysisR-HSA-2730840 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGArrowR-HSA-2396606 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76:PLCGR-HSA-2730851 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76ArrowR-HSA-2396561 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:SLP76R-HSA-2396606 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3ArrowR-HSA-2730885 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:TEC kinases:PIP3R-HSA-2730833 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3ArrowR-HSA-2730888 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-BTK/p-2Y-ITK:PIP3mim-catalysisR-HSA-2730847 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinasesArrowR-HSA-2730858 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-2Y-TEC kinasesR-HSA-2730888 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3ArrowR-HSA-2730833 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3R-HSA-2730858 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAV:p-TEC kinases:PIP3mim-catalysisR-HSA-2730858 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAVArrowR-HSA-2730892 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAVR-HSA-2730841 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCG1:VAVR-HSA-2730885 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGArrowR-HSA-2730851 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1:GADS:p-Y113,Y128,Y145-SLP-76:PLCGR-HSA-2730892 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1ArrowR-HSA-2396599 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1R-HSA-2396561 (Reactome)
p-5Y-LAT:p-SHC1:GRB2:SOS1mim-catalysisR-HSA-2424477 (Reactome)
p-5Y-PKC-theta:DAGArrowR-HSA-2730835 (Reactome)
p-5Y-PKC-theta:DAGR-HSA-2730863 (Reactome)
p-5Y-PKC-theta:DAGmim-catalysisR-HSA-2730863 (Reactome)
p-MAP2K4/p-MAP2K7mim-catalysisR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-168162 (Reactome)
p-MAPK8/9/10ArrowR-HSA-450348 (Reactome)
p-MAPK8/9/10R-HSA-450348 (Reactome)
p-MAPK8/9/10mim-catalysisR-HSA-168136 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOArrowR-HSA-2730876 (Reactome)
p-S177,S181-IKKB:IKKA:NEMOR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOArrowR-HSA-202534 (Reactome)
p-S177,S181-IKKB:IKKA:pUb-NEMOmim-catalysisR-HSA-202541 (Reactome)
p-S257,T261-MAP2K4ArrowR-HSA-2730896 (Reactome)
p-S271,T275-MAP2K7ArrowR-HSA-2730868 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexArrowR-HSA-202541 (Reactome)
p-S32,36-IkB-alpha:NF-kB complexR-HSA-5607728 (Reactome)
p-S552,S645-CARD11R-HSA-2730902 (Reactome)
p-S63,S73-JUNArrowR-HSA-168136 (Reactome)
p-S63,S73-JUNR-HSA-450292 (Reactome)
p-SHC1:GRB2:SOSArrowR-HSA-2730844 (Reactome)
p-SHC1:GRB2:SOSR-HSA-2396599 (Reactome)
p-SHC1:GRB2:SOSR-HSA-2730837 (Reactome)
p-SYK/p-BTKmim-catalysisR-HSA-2730888 (Reactome)
p-T,Y MAPK dimersmim-catalysisR-HSA-450325 (Reactome)
p-T325,T331,S362,S374-FOSArrowR-HSA-450325 (Reactome)
p-T325,T331,S362,S374-FOSR-HSA-450292 (Reactome)
p-Y1400,Y1412-MAP3K1ArrowR-HSA-2730887 (Reactome)
p-Y1400,Y1412-MAP3K1mim-catalysisR-HSA-2730868 (Reactome)
p-Y1400,Y1412-MAP3K1mim-catalysisR-HSA-2730896 (Reactome)
p-Y239,Y240,Y317-SHC1-2ArrowR-HSA-2730886 (Reactome)
p-Y239,Y240,Y317-SHC1-2R-HSA-2730844 (Reactome)
p-Y396-LYNArrowR-HSA-2730862 (Reactome)
p-Y396-LYNR-HSA-2454208 (Reactome)
p-Y396-LYNmim-catalysisR-HSA-2454208 (Reactome)
p-Y90-PKC-theta:DAGArrowR-HSA-2730882 (Reactome)
p-Y90-PKC-theta:DAGR-HSA-2730835 (Reactome)
p21 RAS:GDPR-HSA-2424477 (Reactome)
p21 RAS:GTPArrowR-HSA-2424477 (Reactome)
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