Signaling by the B Cell Receptor (BCR) (Homo sapiens)
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Description
Mature B cells express IgM and IgD immunoglobulins which are complexed at the plasma membrane with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesel et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010).
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006). Source:Reactome.
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Baldock et al. 2000, Irish et al. 2006, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65), BCAP, and CD19 which serve as scaffolds for the assembly of large complexes, the signalosomes, by recruiting phosphoinositol 3-kinase (PI3K), phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
PLC-gamma associated with BLNK hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of calcium ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels in the plasma membrane, resulting in an influx of extracellular calcium ions (Muik et al. 2008, Luik et al. 2008, Park et al. 2009, Mori et al. 2002). PI3K associated with BCAP and CD19 phosphorylates phosphatidylinositol 4,5-bisphosphate to yield phosphatidyinositol 3,4,5-trisphosphate.
Second messengers (calcium, diacylglycerol, inositol 1,4,5-trisphosphate, and phosphatidylinositol 3,4,5-trisphosphate) trigger signaling pathways: NF-kappaB is activated via protein kinase C beta, RAS is activated via RasGRP proteins, NF-AT is activated via calcineurin, and AKT (PKB) is activated via PDK1 (reviewed in Shinohara and Kurosaki 2009, Stone 2006). Source:Reactome.
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- Dowler S, Montalvo L, Cantrell D, Morrice N, Alessi DR.; ''Phosphoinositide 3-kinase-dependent phosphorylation of the dual adaptor for phosphotyrosine and 3-phosphoinositides by the Src family of tyrosine kinase.''; PubMed Europe PMC Scholia
- Blasioli J, Paust S, Thomas ML.; ''Definition of the sites of interaction between the protein tyrosine phosphatase SHP-1 and CD22.''; PubMed Europe PMC Scholia
- Lorenzo PS, Kung JW, Bottorff DA, Garfield SH, Stone JC, Blumberg PM.; ''Phorbol esters modulate the Ras exchange factor RasGRP3.''; PubMed Europe PMC Scholia
- Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu JO, Ke H.; ''Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.''; PubMed Europe PMC Scholia
- Yamashita S, Mochizuki N, Ohba Y, Tobiume M, Okada Y, Sawa H, Nagashima K, Matsuda M.; ''CalDAG-GEFIII activation of Ras, R-ras, and Rap1.''; PubMed Europe PMC Scholia
- Leprince C, Draves KE, Geahlen RL, Ledbetter JA, Clark EA.; ''CD22 associates with the human surface IgM-B-cell antigen receptor complex.''; PubMed Europe PMC Scholia
- Ferguson KM, Kavran JM, Sankaran VG, Fournier E, Isakoff SJ, Skolnik EY, Lemmon MA.; ''Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.''; PubMed Europe PMC Scholia
- Saouaf SJ, Kut SA, Fargnoli J, Rowley RB, Bolen JB, Mahajan S.; ''Reconstitution of the B cell antigen receptor signaling components in COS cells.''; PubMed Europe PMC Scholia
- Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-García ME, Ovechkina YL, Rawlings DJ.; ''Phosphorylation of the CARMA1 linker controls NF-kappaB activation.''; PubMed Europe PMC Scholia
- Engels N, Wollscheid B, Wienands J.; ''Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha.''; PubMed Europe PMC Scholia
- Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM.; ''Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO.''; PubMed Europe PMC Scholia
- Kim LJ, Ferguson HA, Seto AG, Goodrich JA.; ''Characterization of DNA binding, transcriptional activation, and regulated nuclear association of recombinant human NFATp.''; PubMed Europe PMC Scholia
- Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, Ho H, Wang S, Papp E, Bradshaw JM.; ''Molecular mechanism of the Syk activation switch.''; PubMed Europe PMC Scholia
- Rebhun JF, Castro AF, Quilliam LA.; ''Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction.''; PubMed Europe PMC Scholia
- Ozdener F, Dangelmaier C, Ashby B, Kunapuli SP, Daniel JL.; ''Activation of phospholipase Cgamma2 by tyrosine phosphorylation.''; PubMed Europe PMC Scholia
- Cheng KT, Liu X, Ong HL, Ambudkar IS.; ''Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels.''; PubMed Europe PMC Scholia
- Traenckner EB, Wilk S, Baeuerle PA.; ''A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B.''; PubMed Europe PMC Scholia
- Nore BF, Mattsson PT, Antonsson P, Bäckesjö CM, Westlund A, Lennartsson J, Hansson H, Löw P, Rönnstrand L, Smith CI.; ''Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases.''; PubMed Europe PMC Scholia
- Roifman CM, Mills GB, Stewart D, Cheung RK, Grinstein S, Gelfand EW.; ''Response of human B cells to different anti-immunoglobulin isotypes: absence of a correlation between early activation events and cell proliferation.''; PubMed Europe PMC Scholia
- Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, Siemasko K, Chan AC, Aebersold R, Clark MR.; ''The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways.''; PubMed Europe PMC Scholia
- Gold MR, Chan VW, Turck CW, DeFranco AL.; ''Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes.''; PubMed Europe PMC Scholia
- Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C.; ''Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation.''; PubMed Europe PMC Scholia
- Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
- Rolli V, Gallwitz M, Wossning T, Flemming A, Schamel WW, Zürn C, Reth M.; ''Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop.''; PubMed Europe PMC Scholia
- Hanasaki K, Powell LD, Varki A.; ''Binding of human plasma sialoglycoproteins by the B cell-specific lectin CD22. Selective recognition of immunoglobulin M and haptoglobin.''; PubMed Europe PMC Scholia
- Nisitani S, Kato RM, Rawlings DJ, Witte ON, Wahl MI.; ''In situ detection of activated Bruton's tyrosine kinase in the Ig signaling complex by phosphopeptide-specific monoclonal antibodies.''; PubMed Europe PMC Scholia
- Kunkel HG.; ''Surface markers of human lymphocytes.''; PubMed Europe PMC Scholia
- Bohnenberger H, Oellerich T, Engelke M, Hsiao HH, Urlaub H, Wienands J.; ''Complex phosphorylation dynamics control the composition of the Syk interactome in B cells.''; PubMed Europe PMC Scholia
- Li Z, Nabel GJ.; ''A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription.''; PubMed Europe PMC Scholia
- Rodriguez R, Matsuda M, Perisic O, Bravo J, Paul A, Jones NP, Light Y, Swann K, Williams RL, Katan M.; ''Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling.''; PubMed Europe PMC Scholia
- Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC.; ''BLNK: molecular scaffolding through 'cis'-mediated organization of signaling proteins.''; PubMed Europe PMC Scholia
- Alland L, Peseckis SM, Atherton RE, Berthiaume L, Resh MD.; ''Dual myristylation and palmitylation of Src family member p59fyn affects subcellular localization.''; PubMed Europe PMC Scholia
- Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT.; ''Inhibition of the B cell by CD22: a requirement for Lyn.''; PubMed Europe PMC Scholia
- Sanchez M, Misulovin Z, Burkhardt AL, Mahajan S, Costa T, Franke R, Bolen JB, Nussenzweig M.; ''Signal transduction by immunoglobulin is mediated through Ig alpha and Ig beta.''; PubMed Europe PMC Scholia
- Wu C, Ghosh S.; ''beta-TrCP mediates the signal-induced ubiquitination of IkappaBbeta.''; PubMed Europe PMC Scholia
- Okamura H, Aramburu J, García-Rodríguez C, Viola JP, Raghavan A, Tahiliani M, Zhang X, Qin J, Hogan PG, Rao A.; ''Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity.''; PubMed Europe PMC Scholia
- Lin L, Czerwinski R, Kelleher K, Siegel MM, Wu P, Kriz R, Aulabaugh A, Stahl M.; ''Activation loop phosphorylation modulates Bruton's tyrosine kinase (Btk) kinase domain activity.''; PubMed Europe PMC Scholia
- Nel AE, Landreth GE, Goldschmidt-Clermont PJ, Tung HE, Galbraith RM.; ''Enhanced tyrosine phosphorylation in B lymphocytes upon complexing of membrane immunoglobulin.''; PubMed Europe PMC Scholia
- Padeh S, Levitzki A, Gazit A, Mills GB, Roifman CM.; ''Activation of phospholipase C in human B cells is dependent on tyrosine phosphorylation.''; PubMed Europe PMC Scholia
- Roose JP, Mollenauer M, Ho M, Kurosaki T, Weiss A.; ''Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes.''; PubMed Europe PMC Scholia
- Han S, Collins BE, Bengtson P, Paulson JC.; ''Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking.''; PubMed Europe PMC Scholia
- Salim K, Bottomley MJ, Querfurth E, Zvelebil MJ, Gout I, Scaife R, Margolis RL, Gigg R, Smith CI, Driscoll PC, Waterfield MD, Panayotou G.; ''Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase.''; PubMed Europe PMC Scholia
- Wienands J, Schweikert J, Wollscheid B, Jumaa H, Nielsen PJ, Reth M.; ''SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation.''; PubMed Europe PMC Scholia
- Brezski RJ, Monroe JG.; ''B-cell receptor.''; PubMed Europe PMC Scholia
- Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS.; ''Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation.''; PubMed Europe PMC Scholia
- Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S, Tarakhovsky A.; ''Immunodeficiency in protein kinase cbeta-deficient mice.''; PubMed Europe PMC Scholia
- Burke JR, Wood MK, Ryseck RP, Walther S, Meyers CA.; ''Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2.''; PubMed Europe PMC Scholia
- Vasile S, Coligan JE, Yoshida M, Seon BK.; ''Isolation and chemical characterization of the human B29 and mb-1 proteins of the B cell antigen receptor complex.''; PubMed Europe PMC Scholia
- Wienands J, Hombach J, Radbruch A, Riesterer C, Reth M.; ''Molecular components of the B cell antigen receptor complex of class IgD differ partly from those of IgM.''; PubMed Europe PMC Scholia
- Fu C, Chan AC.; ''Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation.''; PubMed Europe PMC Scholia
- Roose JP, Mollenauer M, Gupta VA, Stone J, Weiss A.; ''A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells.''; PubMed Europe PMC Scholia
- Blank V, Kourilsky P, Israël A.; ''Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus.''; PubMed Europe PMC Scholia
- McConnell FM, Shears SB, Lane PJ, Scheibel MS, Clark EA.; ''Relationships between the degree of cross-linking of surface immunoglobulin and the associated inositol 1,4,5-trisphosphate and Ca2+ signals in human B cells.''; PubMed Europe PMC Scholia
- Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
- Brooks SR, Li X, Volanakis EJ, Carter RH.; ''Systematic analysis of the role of CD19 cytoplasmic tyrosines in enhancement of activation in Daudi human B cells: clustering of phospholipase C and Vav and of Grb2 and Sos with different CD19 tyrosines.''; PubMed Europe PMC Scholia
- Su TT, Guo B, Kawakami Y, Sommer K, Chae K, Humphries LA, Kato RM, Kang S, Patrone L, Wall R, Teitell M, Leitges M, Kawakami T, Rawlings DJ.; ''PKC-beta controls I kappa B kinase lipid raft recruitment and activation in response to BCR signaling.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
26S proteasome | Complex | R-HSA-68819 (Reactome) | |
4xCa2+:CaM | Complex | R-HSA-74294 (Reactome) | |
ADP | Metabolite | CHEBI:16761 (ChEBI) | |
AHCYL1 | Protein | O43865 (Uniprot-TrEMBL) | |
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramer | Complex | R-HSA-5226920 (Reactome) | |
ATP | Metabolite | CHEBI:15422 (ChEBI) | |
Activated PKC beta | Complex | R-HSA-139829 (Reactome) | |
Active IKK complex | Complex | R-HSA-727820 (Reactome) | |
Antigen:BCR | Complex | R-HSA-983689 (Reactome) | |
Antigen:p-BCR:SYK | Complex | R-HSA-983693 (Reactome) | |
Antigen:p-BCR:p-SYK:p-BLNK | Complex | R-HSA-983687 (Reactome) | |
Antigen:p-BCR:p-SYK | Complex | R-HSA-983690 (Reactome) | |
Antigen:p-BCR | Complex | R-HSA-983691 (Reactome) | |
Antigen | R-NUL-983667 (Reactome) | ||
BCAP Signalosome | Complex | R-HSA-2045909 (Reactome) | |
BCR | Complex | R-HSA-983677 (Reactome) | |
BLK-like proteins | R-HSA-3902518 (Reactome) | This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis. | |
BLK | Protein | P51451 (Uniprot-TrEMBL) | |
BLNK (SLP-65) Signalosome | Complex | R-HSA-984818 (Reactome) | |
BLNK | Protein | Q8WV28 (Uniprot-TrEMBL) | |
BLNK:GRB2:SOS1:CIN85:CBL | Complex | R-HSA-983692 (Reactome) | |
BTK | Protein | Q06187 (Uniprot-TrEMBL) | |
BTRC | Protein | Q9Y297 (Uniprot-TrEMBL) | |
CALM1 | Protein | P62158 (Uniprot-TrEMBL) | |
CALM1 | Protein | P62158 (Uniprot-TrEMBL) | |
CARD11 | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
CARMA1 oligomer | Complex | R-HSA-1169088 (Reactome) | |
CARMA1:BCL10:MALT1:TAK1:IKK | Complex | R-HSA-1168620 (Reactome) | TAK1 and the IKK complex are observed to migrate to lipid rafts containing phosphorylated CARMA1, BCL10, and MALT1. By analogy with NF-kappaB signaling pathways in other cells, the CARMA1:BCL10MALT1:TAK1:IKK complex in B cells may also contain TAB1, TAB2 and/or TAB3, TRAF6. |
CARMA1:BCL10:MALT1:TAK1 | Complex | R-HSA-1168619 (Reactome) | TAK1 and the IKK complex are observed to migrate to lipid rafts containing phosphorylated CARMA1, BCL10, and MALT1. By analogy with NF-kappaB signaling pathways in other cells, the CARMA1:BCL10MALT1:TAK1:IKK complex in B cells may also contain TAB1, TAB2 and/or TAB3, TRAF6. |
CARMA1:MALT1:BCL10 | Complex | R-HSA-1168622 (Reactome) | |
CBL | Protein | P22681 (Uniprot-TrEMBL) | |
CBLB | Protein | Q13191 (Uniprot-TrEMBL) | |
CD19 | Protein | P15391 (Uniprot-TrEMBL) | |
CD19 Signalosome | Complex | R-HSA-2076233 (Reactome) | |
CD19:VAV1 | Complex | R-HSA-2076225 (Reactome) | |
CD79A | Protein | P11912 (Uniprot-TrEMBL) | |
CD79B | Protein | P40259 (Uniprot-TrEMBL) | |
CHUK | Protein | O15111 (Uniprot-TrEMBL) | |
CRAC channel | Complex | R-HSA-434679 (Reactome) | |
CUL1 | Protein | Q13616 (Uniprot-TrEMBL) | |
Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
Calcineurin (CaN) | Complex | R-HSA-2025977 (Reactome) | |
Calcineurin:Phosphorylated NFATC1,2,3 | Complex | R-HSA-2025899 (Reactome) | |
Cyclophilin A:Cyclosporin A | Complex | R-HSA-2026008 (Reactome) | |
Cyclosporin A | Metabolite | CHEBI:4031 (ChEBI) | |
DAG | Metabolite | CHEBI:17815 (ChEBI) | |
DAG | CHEBI:17815 (ChEBI) | ||
DAPP1 | Protein | Q9UN19 (Uniprot-TrEMBL) | |
Dephosphorylated NFATC1,2,3 | R-HSA-2025852 (Reactome) | ||
FBXW11 | Protein | Q9UKB1 (Uniprot-TrEMBL) | |
FKBP1A | Protein | P62942 (Uniprot-TrEMBL) | |
FKBP1A:Tacrolimus | Complex | R-HSA-2026019 (Reactome) | |
FYN | Protein | P06241 (Uniprot-TrEMBL) | |
Fe3+ | Metabolite | CHEBI:29034 (ChEBI) | |
GDP | Metabolite | CHEBI:17552 (ChEBI) | |
GRB2-1 | Protein | P62993-1 (Uniprot-TrEMBL) | |
GRB2-1 | Protein | P62993-1 (Uniprot-TrEMBL) | |
GTP | Metabolite | CHEBI:15996 (ChEBI) | |
HRAS | Protein | P01112 (Uniprot-TrEMBL) | |
I(1,4,5)P3 | Metabolite | CHEBI:16595 (ChEBI) | |
I(1,4,5)P3 | Metabolite | CHEBI:16595 (ChEBI) | |
IGHD | Protein | P01880 (Uniprot-TrEMBL) | |
IGHM | Protein | P01871 (Uniprot-TrEMBL) | |
IGHV(1-?) | Protein | A2KUC3 (Uniprot-TrEMBL) | |
IGHV7-81(1-?) | Protein | Q6PIL0 (Uniprot-TrEMBL) | |
IGKC | Protein | P01834 (Uniprot-TrEMBL) | |
IGKV1-5(23-?) | Protein | P01602 (Uniprot-TrEMBL) | |
IGKV4-1(21-?) | Protein | P06312 (Uniprot-TrEMBL) | |
IGKVA18(21-?) | Protein | A2NJV5 (Uniprot-TrEMBL) | |
IGLC1 | Protein | P0CG04 (Uniprot-TrEMBL) | |
IGLC2 | Protein | P0CG05 (Uniprot-TrEMBL) | |
IGLC3 | Protein | P0CG06 (Uniprot-TrEMBL) | |
IGLC6 | Protein | P0CF74 (Uniprot-TrEMBL) | |
IGLC7 | Protein | A0M8Q6 (Uniprot-TrEMBL) | |
IGLV(23-?) | Protein | A2NXD2 (Uniprot-TrEMBL) | |
IKBKB | Protein | O14920 (Uniprot-TrEMBL) | |
IKBKG | Protein | Q9Y6K9 (Uniprot-TrEMBL) | |
IKKA | Protein | O15111 (Uniprot-TrEMBL) | |
IKKA:IKBKB:IKBKG | Complex | R-HSA-168113 (Reactome) | |
IP3 receptor homotetramer | Complex | R-HSA-169686 (Reactome) | |
ITPR1 | Protein | Q14643 (Uniprot-TrEMBL) | |
ITPR2 | Protein | Q14571 (Uniprot-TrEMBL) | |
ITPR3 | Protein | Q14573 (Uniprot-TrEMBL) | |
ITPR:I(1,4,5)P3 tetramer | Complex | R-HSA-169696 (Reactome) | |
Ig heavy chain V-I region EU | Protein | P01742 (Uniprot-TrEMBL) | |
Ig heavy chain V-I region HG3 | Protein | P01743 (Uniprot-TrEMBL) | |
Ig heavy chain V-I region Mot | Protein | P06326 (Uniprot-TrEMBL) | |
Ig heavy chain V-I region ND | Protein | P01744 (Uniprot-TrEMBL) | |
Ig heavy chain V-I region SIE | Protein | P01761 (Uniprot-TrEMBL) | |
Ig heavy chain V-I region WOL | Protein | P01760 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region ARH-77 | Protein | P06331 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region COR | Protein | P01815 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region DAW | Protein | P01816 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region HE | Protein | P01818 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region MCE | Protein | P01817 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region NEWM | Protein | P01825 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region OU | Protein | P01814 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region SESS | Protein | P04438 (Uniprot-TrEMBL) | |
Ig heavy chain V-II region WAH | Protein | P01824 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region BRO | Protein | P01766 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region BUR | Protein | P01773 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region BUT | Protein | P01767 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region CAM | Protein | P01768 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region DOB | Protein | P01782 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region GA | Protein | P01769 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region GAL | Protein | P01781 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region HIL | Protein | P01771 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region JON | Protein | P01780 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region KOL | Protein | P01772 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region LAY | Protein | P01775 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region NIE | Protein | P01770 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region POM | Protein | P01774 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region TEI | Protein | P01777 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region TIL | Protein | P01765 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region TRO | Protein | P01762 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region TUR | Protein | P01779 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region WAS | Protein | P01776 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region WEA | Protein | P01763 (Uniprot-TrEMBL) | |
Ig heavy chain V-III region ZAP | Protein | P01778 (Uniprot-TrEMBL) | |
Ig kappa chain V region EV15 | Protein | P06315 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region AG | Protein | P01593 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region AU | Protein | P01594 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region BAN | Protein | P04430 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Bi | Protein | P01595 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region CAR | Protein | P01596 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region DEE | Protein | P01597 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Daudi | Protein | P04432 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region EU | Protein | P01598 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Gal | Protein | P01599 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region HK101 | Protein | P01601 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Hau | Protein | P01600 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Ka | Protein | P01603 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Kue | Protein | P01604 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Lay | Protein | P01605 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Mev | Protein | P01612 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Ni | Protein | P01613 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region OU | Protein | P01606 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Rei | Protein | P01607 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Roy | Protein | P01608 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Scw | Protein | P01609 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region WAT | Protein | P80362 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region WEA | Protein | P01610 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Walker | Protein | P04431 (Uniprot-TrEMBL) | |
Ig kappa chain V-I region Wes | Protein | P01611 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region Cum | Protein | P01614 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region FR | Protein | P01615 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region GM607 | Protein | P06309 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region MIL | Protein | P01616 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region RPMI 6410 | Protein | P06310 (Uniprot-TrEMBL) | |
Ig kappa chain V-II region TEW | Protein | P01617 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region B6 | Protein | P01619 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region CLL | Protein | P04207 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region GOL | Protein | P04206 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region HAH | Protein | P18135 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region HIC | Protein | P18136 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region IARC/BL41 | Protein | P06311 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region NG9 | Protein | P01621 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region POM | Protein | P01624 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region SIE | Protein | P01620 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region Ti | Protein | P01622 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region VG | Protein | P04433 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region VH | Protein | P04434 (Uniprot-TrEMBL) | |
Ig kappa chain V-III region WOL | Protein | P01623 (Uniprot-TrEMBL) | |
Ig kappa chain V-IV region B17 | Protein | P06314 (Uniprot-TrEMBL) | |
Ig kappa chain V-IV region JI | Protein | P06313 (Uniprot-TrEMBL) | |
Ig kappa chain V-IV region Len | Protein | P01625 (Uniprot-TrEMBL) | |
Ig kappa chain V-IV region STH | Protein | P83593 (Uniprot-TrEMBL) | |
Ig lambda chain V-III region LOI | Protein | P80748 (Uniprot-TrEMBL) | |
Ig lambda chain V-III region SH | Protein | P01714 (Uniprot-TrEMBL) | |
Ig lambda chain V-VII region MOT | Protein | P01720 (Uniprot-TrEMBL) | |
Ig lambda chain V region 4A | Protein | P04211 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region BL2 | Protein | P06316 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region EPS | Protein | P06888 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region HA | Protein | P01700 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region MEM | Protein | P06887 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region NEW | Protein | P01701 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region NEWM | Protein | P01703 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region NIG-64 | Protein | P01702 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region VOR | Protein | P01699 (Uniprot-TrEMBL) | |
Ig lambda chain V-I region WAH | Protein | P04208 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region BO | Protein | P01710 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region BOH | Protein | P01706 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region BUR | Protein | P01708 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region MGC | Protein | P01709 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region NEI | Protein | P01705 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region NIG-58 | Protein | P01713 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region NIG-84 | Protein | P04209 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region TOG | Protein | P01704 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region TRO | Protein | P01707 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region VIL | Protein | P01711 (Uniprot-TrEMBL) | |
Ig lambda chain V-II region WIN | Protein | P01712 (Uniprot-TrEMBL) | |
Ig lambda chain V-IV region Bau | Protein | P01715 (Uniprot-TrEMBL) | |
Ig lambda chain V-IV region Hil | Protein | P01717 (Uniprot-TrEMBL) | |
Ig lambda chain V-IV region Kern | Protein | P01718 (Uniprot-TrEMBL) | |
Ig lambda chain V-IV region MOL | Protein | P06889 (Uniprot-TrEMBL) | |
Ig lambda chain V-IV region X | Protein | P01716 (Uniprot-TrEMBL) | |
Ig lambda chain V-V region DEL | Protein | P01719 (Uniprot-TrEMBL) | |
Ig lambda chain V-VI region AR | Protein | P01721 (Uniprot-TrEMBL) | |
Ig lambda chain V-VI region EB4 | Protein | P06319 (Uniprot-TrEMBL) | |
Ig lambda chain V-VI region NIG-48 | Protein | P01722 (Uniprot-TrEMBL) | |
Ig lambda chain V-VI region SUT | Protein | P06317 (Uniprot-TrEMBL) | |
Ig lambda chain V-VI region WLT | Protein | P06318 (Uniprot-TrEMBL) | |
IgH heavy chain
V-III region VH26 precursor | Protein | P01764 (Uniprot-TrEMBL) | |
KRAS | Protein | P01116 (Uniprot-TrEMBL) | |
LYN | Protein | P07948 (Uniprot-TrEMBL) | |
MALT1 | Protein | Q9UDY8 (Uniprot-TrEMBL) | |
MALT1 | Protein | Q9UDY8 (Uniprot-TrEMBL) | |
MAP3K7 | Protein | O43318 (Uniprot-TrEMBL) | |
NAD+ | Metabolite | CHEBI:15846 (ChEBI) | |
NCK1 | Protein | P16333 (Uniprot-TrEMBL) | |
NCK1 | Protein | P16333 (Uniprot-TrEMBL) | |
NF-kappa-B p50,p65,c-Rel:IKB | R-HSA-1168593 (Reactome) | ||
NF-kappa-B p50,p65,c-Rel:p-IKB | R-HSA-1168588 (Reactome) | ||
NF-kappaB p50,p65,c-Rel dimer | R-HSA-1168598 (Reactome) | ||
NF-kappaB p50,p65,c-Rel dimer | R-HSA-1168608 (Reactome) | ||
NF-kappaB p50,p65,c-Rel:ub-p-IKB | R-HSA-1168613 (Reactome) | ||
NF-kappaB:p-IkB:SCF-betaTrCP | Complex | R-HSA-1168617 (Reactome) | |
NFKB1(1-433) | Protein | P19838 (Uniprot-TrEMBL) | |
NRAS | Protein | P01111 (Uniprot-TrEMBL) | |
ORAI1 | Protein | Q96D31 (Uniprot-TrEMBL) | |
Orai1 dimer | Complex | R-HSA-434696 (Reactome) | |
PI(3,4,5)P3 | Metabolite | CHEBI:16618 (ChEBI) | |
PI(3,4,5)P3 | Metabolite | CHEBI:16618 (ChEBI) | |
PI(4,5)P2 | Metabolite | CHEBI:18348 (ChEBI) | |
PIK3AP1 | Protein | Q6ZUJ8 (Uniprot-TrEMBL) | |
PIK3CD | Protein | O00329 (Uniprot-TrEMBL) | |
PIK3CD:PIK3R1 | Complex | R-HSA-1045152 (Reactome) | |
PIK3CD:PIK3R1 | Complex | R-HSA-1806213 (Reactome) | |
PIK3R1 | Protein | P27986 (Uniprot-TrEMBL) | |
PIP3 activates AKT signaling | Pathway | R-HSA-1257604 (Reactome) | Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. |
PLC gamma1,2 | R-HSA-1169089 (Reactome) | ||
PPIA | Protein | P62937 (Uniprot-TrEMBL) | |
PPP3CA | Protein | Q08209 (Uniprot-TrEMBL) | |
PPP3CB | Protein | P16298 (Uniprot-TrEMBL) | |
PPP3R1 | Protein | P63098 (Uniprot-TrEMBL) | |
PRKCB | Protein | P05771 (Uniprot-TrEMBL) | |
PRKCB | Protein | P05771 (Uniprot-TrEMBL) | |
PSMA1 | Protein | P25786 (Uniprot-TrEMBL) | |
PSMA2 | Protein | P25787 (Uniprot-TrEMBL) | |
PSMA3 | Protein | P25788 (Uniprot-TrEMBL) | |
PSMA4 | Protein | P25789 (Uniprot-TrEMBL) | |
PSMA5 | Protein | P28066 (Uniprot-TrEMBL) | |
PSMA6 | Protein | P60900 (Uniprot-TrEMBL) | |
PSMA7 | Protein | O14818 (Uniprot-TrEMBL) | |
PSMA8 | Protein | Q8TAA3 (Uniprot-TrEMBL) | |
PSMB1 | Protein | P20618 (Uniprot-TrEMBL) | |
PSMB10 | Protein | P40306 (Uniprot-TrEMBL) | |
PSMB11 | Protein | A5LHX3 (Uniprot-TrEMBL) | |
PSMB2 | Protein | P49721 (Uniprot-TrEMBL) | |
PSMB3 | Protein | P49720 (Uniprot-TrEMBL) | |
PSMB4 | Protein | P28070 (Uniprot-TrEMBL) | |
PSMB5 | Protein | P28074 (Uniprot-TrEMBL) | |
PSMB6 | Protein | P28072 (Uniprot-TrEMBL) | |
PSMB7 | Protein | Q99436 (Uniprot-TrEMBL) | |
PSMB8 | Protein | P28062 (Uniprot-TrEMBL) | |
PSMB9 | Protein | P28065 (Uniprot-TrEMBL) | |
PSMC1 | Protein | P62191 (Uniprot-TrEMBL) | |
PSMC2 | Protein | P35998 (Uniprot-TrEMBL) | |
PSMC3 | Protein | P17980 (Uniprot-TrEMBL) | |
PSMC4 | Protein | P43686 (Uniprot-TrEMBL) | |
PSMC5 | Protein | P62195 (Uniprot-TrEMBL) | |
PSMC6 | Protein | P62333 (Uniprot-TrEMBL) | |
PSMD1 | Protein | Q99460 (Uniprot-TrEMBL) | |
PSMD10 | Protein | O75832 (Uniprot-TrEMBL) | |
PSMD11 | Protein | O00231 (Uniprot-TrEMBL) | |
PSMD12 | Protein | O00232 (Uniprot-TrEMBL) | |
PSMD13 | Protein | Q9UNM6 (Uniprot-TrEMBL) | |
PSMD14 | Protein | O00487 (Uniprot-TrEMBL) | |
PSMD2 | Protein | Q13200 (Uniprot-TrEMBL) | |
PSMD3 | Protein | O43242 (Uniprot-TrEMBL) | |
PSMD4 | Protein | P55036 (Uniprot-TrEMBL) | |
PSMD5 | Protein | Q16401 (Uniprot-TrEMBL) | |
PSMD6 | Protein | Q15008 (Uniprot-TrEMBL) | |
PSMD7 | Protein | P51665 (Uniprot-TrEMBL) | |
PSMD8 | Protein | P48556 (Uniprot-TrEMBL) | |
PSMD9 | Protein | O00233 (Uniprot-TrEMBL) | |
PSME1 | Protein | Q06323 (Uniprot-TrEMBL) | |
PSME2 | Protein | Q9UL46 (Uniprot-TrEMBL) | |
PSME3 | Protein | P61289 (Uniprot-TrEMBL) | |
PSME4 | Protein | Q14997 (Uniprot-TrEMBL) | |
PSMF1 | Protein | Q92530 (Uniprot-TrEMBL) | |
PTPN6 | Protein | P29350 (Uniprot-TrEMBL) | |
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCR | Complex | R-HSA-5690677 (Reactome) | |
Phosphatidylserine | Metabolite | CHEBI:18303 (ChEBI) | |
Phosphatidylserine | CHEBI:18303 (ChEBI) | ||
Phosphorylated NFATC1,2,3 | R-HSA-2025924 (Reactome) | ||
RASGRP1,3 | R-HSA-1169462 (Reactome) | ||
REL | Protein | Q04864 (Uniprot-TrEMBL) | |
RELA | Protein | Q04206 (Uniprot-TrEMBL) | |
SCF-beta-TrCp1,2 | R-HSA-1168601 (Reactome) | ||
SH3KBP1 | Protein | Q96B97 (Uniprot-TrEMBL) | |
SHC1 p46,p52 | R-HSA-1169480 (Reactome) | SHC1 isoforms p46 and p52 are found in B cells (Smit et al. 1994). | |
SKP1 | Protein | P63208 (Uniprot-TrEMBL) | |
SOS1 | Protein | Q07889 (Uniprot-TrEMBL) | |
STIM1 Dimer | Complex | R-HSA-1168370 (Reactome) | |
STIM1 | Protein | Q13586 (Uniprot-TrEMBL) | |
STIM1:Calcium | Complex | R-HSA-1168371 (Reactome) | |
STIM1:TRPC1 | Complex | R-HSA-2089954 (Reactome) | |
SYK | Protein | P43405 (Uniprot-TrEMBL) | |
SYK | Protein | P43405 (Uniprot-TrEMBL) | |
TRPC1 | Protein | P48995 (Uniprot-TrEMBL) | |
TRPC1 | Protein | P48995 (Uniprot-TrEMBL) | |
Tacrolimus | Metabolite | CHEBI:61049 (ChEBI) | |
Ub | R-HSA-113595 (Reactome) | ||
VAV1 | Protein | P15498 (Uniprot-TrEMBL) | |
VAV1 | Protein | P15498 (Uniprot-TrEMBL) | |
Zn2+ | Metabolite | CHEBI:29105 (ChEBI) | |
p-12S-NFATC1 | Protein | O95644 (Uniprot-TrEMBL) | |
p-13S-NFATC3 | Protein | Q12968 (Uniprot-TrEMBL) | |
p-14S-NFATC2 | Protein | Q13469 (Uniprot-TrEMBL) | |
p-4Y-PIK3AP1 | Protein | Q6ZUJ8 (Uniprot-TrEMBL) | |
p-5Y-BLNK | Protein | Q8WV28 (Uniprot-TrEMBL) | |
p-6Y-CD19 | Protein | P15391 (Uniprot-TrEMBL) | |
p-6Y-SYK | Protein | P43405 (Uniprot-TrEMBL) | |
p-BCL10 | Protein | O95999 (Uniprot-TrEMBL) | |
p-BCL10 | Protein | O95999 (Uniprot-TrEMBL) | |
p-CARMA1 Oligomer | Complex | R-HSA-1168616 (Reactome) | The coiled coil (CC) domain of CARMA1 interacts with the CC domain on other CARMA1 molecules to form oligomers of unknown stoichiometry. |
p-RASGRP1,3:DAG | Complex | R-HSA-1168369 (Reactome) | RasGRP3 binds diacylglycerol via its C1 domain. |
p-S157,S161-NFKBIE | Protein | O00221 (Uniprot-TrEMBL) | |
p-S177,S181-IKBKB | Protein | O14920 (Uniprot-TrEMBL) | |
p-S19,S23-NFKBIB | Protein | Q15653 (Uniprot-TrEMBL) | |
p-S32,S36-NFKBIA | Protein | P25963 (Uniprot-TrEMBL) | |
p-S559,S644,S652-CARD11 | Protein | Q9BXL7 (Uniprot-TrEMBL) | |
p-T133-RASGRP3 | Protein | Q8IV61 (Uniprot-TrEMBL) | |
p-T184-RASGRP1 | Protein | O95267 (Uniprot-TrEMBL) | |
p-T187-MAP3K7 | Protein | O43318 (Uniprot-TrEMBL) | |
p-Y139-DAPP1 | Protein | Q9UN19 (Uniprot-TrEMBL) | |
p-Y188,Y199-CD79A | Protein | P11912 (Uniprot-TrEMBL) | |
p-Y194,Y195,Y272-SHC1-1(156-583) | Protein | P29353-3 (Uniprot-TrEMBL) | |
p-Y196,Y207-CD79B | Protein | P40259 (Uniprot-TrEMBL) | By homology with CD79A (Ig-alpha), CD79B (Ig-beta) is presumed to be phosphorylated on tyrosines 196 and 207. |
p-Y223,Y551-BTK | Protein | Q06187 (Uniprot-TrEMBL) | |
p-Y239,Y240,Y317-SHC1-2 | Protein | P29353-2 (Uniprot-TrEMBL) | |
p-Y753,Y759,Y1217-PLCG2 | Protein | P16885 (Uniprot-TrEMBL) | |
p-Y762,807,822-CD22 | Protein | P20273 (Uniprot-TrEMBL) | |
p-Y771,Y783-PLCG1 | Protein | P19174 (Uniprot-TrEMBL) | |
p21 RAS:GDP | Complex | R-HSA-109796 (Reactome) | |
p21 RAS:GTP | Complex | R-HSA-109783 (Reactome) |
Annotated Interactions
View all... |
Source | Target | Type | Database reference | Comment |
---|---|---|---|---|
26S proteasome | mim-catalysis | R-HSA-1168640 (Reactome) | ||
4xCa2+:CaM | Arrow | R-HSA-74448 (Reactome) | ||
4xCa2+:CaM | R-HSA-2025890 (Reactome) | |||
ADP | Arrow | R-HSA-1168374 (Reactome) | ||
ADP | Arrow | R-HSA-1168635 (Reactome) | ||
ADP | Arrow | R-HSA-1168638 (Reactome) | ||
ADP | Arrow | R-HSA-1168641 (Reactome) | ||
ADP | Arrow | R-HSA-983703 (Reactome) | ||
ADP | Arrow | R-HSA-983707 (Reactome) | ||
ADP | Arrow | R-HSA-983709 (Reactome) | ||
AHCYL1:NAD+:ITPR1:I(1,4,5)P3 tetramer | TBar | R-HSA-169683 (Reactome) | ||
ATP | R-HSA-1168374 (Reactome) | |||
ATP | R-HSA-1168635 (Reactome) | |||
ATP | R-HSA-1168638 (Reactome) | |||
ATP | R-HSA-1168641 (Reactome) | |||
ATP | R-HSA-983703 (Reactome) | |||
ATP | R-HSA-983707 (Reactome) | |||
ATP | R-HSA-983709 (Reactome) | |||
Activated PKC beta | Arrow | R-HSA-1168373 (Reactome) | ||
Activated PKC beta | mim-catalysis | R-HSA-1168635 (Reactome) | ||
Active IKK complex | Arrow | R-HSA-1168641 (Reactome) | ||
Active IKK complex | mim-catalysis | R-HSA-1168638 (Reactome) | ||
Antigen:BCR | Arrow | R-HSA-983696 (Reactome) | ||
Antigen:BCR | R-HSA-983709 (Reactome) | |||
Antigen:p-BCR:SYK | Arrow | R-HSA-983700 (Reactome) | ||
Antigen:p-BCR:SYK | R-HSA-983707 (Reactome) | |||
Antigen:p-BCR:p-SYK:p-BLNK | Arrow | R-HSA-983703 (Reactome) | ||
Antigen:p-BCR:p-SYK:p-BLNK | R-HSA-983704 (Reactome) | |||
Antigen:p-BCR:p-SYK:p-BLNK | mim-catalysis | R-HSA-983704 (Reactome) | ||
Antigen:p-BCR:p-SYK | Arrow | R-HSA-983707 (Reactome) | ||
Antigen:p-BCR:p-SYK | R-HSA-983703 (Reactome) | |||
Antigen:p-BCR:p-SYK | mim-catalysis | R-HSA-983703 (Reactome) | ||
Antigen:p-BCR:p-SYK | mim-catalysis | R-HSA-983707 (Reactome) | ||
Antigen:p-BCR | Arrow | R-HSA-983709 (Reactome) | ||
Antigen:p-BCR | R-HSA-983700 (Reactome) | |||
Antigen | R-HSA-983696 (Reactome) | |||
BCAP Signalosome | Arrow | R-HSA-983704 (Reactome) | ||
BCAP Signalosome | mim-catalysis | R-HSA-2045911 (Reactome) | ||
BCR | R-HSA-983696 (Reactome) | |||
BLK-like proteins | mim-catalysis | R-HSA-983709 (Reactome) | ||
BLNK (SLP-65) Signalosome | Arrow | R-HSA-983704 (Reactome) | ||
BLNK (SLP-65) Signalosome | mim-catalysis | R-HSA-1112666 (Reactome) | ||
BLNK:GRB2:SOS1:CIN85:CBL | R-HSA-983703 (Reactome) | |||
BTK | R-HSA-983704 (Reactome) | |||
BTK | mim-catalysis | R-HSA-983704 (Reactome) | ||
CALM1 | R-HSA-74448 (Reactome) | |||
CARMA1 oligomer | R-HSA-1168635 (Reactome) | |||
CARMA1:BCL10:MALT1:TAK1:IKK | Arrow | R-HSA-1168637 (Reactome) | ||
CARMA1:BCL10:MALT1:TAK1:IKK | R-HSA-1168641 (Reactome) | |||
CARMA1:BCL10:MALT1:TAK1:IKK | mim-catalysis | R-HSA-1168641 (Reactome) | ||
CARMA1:BCL10:MALT1:TAK1 | Arrow | R-HSA-1168641 (Reactome) | ||
CARMA1:MALT1:BCL10 | Arrow | R-HSA-1168644 (Reactome) | ||
CARMA1:MALT1:BCL10 | R-HSA-1168637 (Reactome) | |||
CD19 Signalosome | Arrow | R-HSA-983704 (Reactome) | ||
CD19 Signalosome | mim-catalysis | R-HSA-2076220 (Reactome) | ||
CD19:VAV1 | R-HSA-983704 (Reactome) | |||
CRAC channel | Arrow | R-HSA-434700 (Reactome) | ||
CRAC channel | mim-catalysis | R-HSA-434798 (Reactome) | ||
Ca2+ | Arrow | R-HSA-1168376 (Reactome) | ||
Ca2+ | Arrow | R-HSA-169683 (Reactome) | ||
Ca2+ | Arrow | R-HSA-2089943 (Reactome) | ||
Ca2+ | Arrow | R-HSA-434798 (Reactome) | ||
Ca2+ | R-HSA-1168373 (Reactome) | |||
Ca2+ | R-HSA-169683 (Reactome) | |||
Ca2+ | R-HSA-2025890 (Reactome) | |||
Ca2+ | R-HSA-2089943 (Reactome) | |||
Ca2+ | R-HSA-434798 (Reactome) | |||
Ca2+ | R-HSA-74448 (Reactome) | |||
Calcineurin (CaN) | R-HSA-2025890 (Reactome) | |||
Calcineurin:Phosphorylated NFATC1,2,3 | Arrow | R-HSA-2025890 (Reactome) | ||
Calcineurin:Phosphorylated NFATC1,2,3 | R-HSA-2025882 (Reactome) | |||
Calcineurin:Phosphorylated NFATC1,2,3 | mim-catalysis | R-HSA-2025882 (Reactome) | ||
Cyclophilin A:Cyclosporin A | TBar | R-HSA-2025882 (Reactome) | ||
DAG | Arrow | R-HSA-1112666 (Reactome) | ||
DAG | R-HSA-1168373 (Reactome) | |||
DAG | R-HSA-1168374 (Reactome) | |||
DAPP1 | R-HSA-983704 (Reactome) | |||
Dephosphorylated NFATC1,2,3 | Arrow | R-HSA-2025882 (Reactome) | ||
FKBP1A:Tacrolimus | TBar | R-HSA-2025882 (Reactome) | ||
FYN | mim-catalysis | R-HSA-983709 (Reactome) | ||
GRB2-1 | R-HSA-983704 (Reactome) | |||
I(1,4,5)P3 | Arrow | R-HSA-1112666 (Reactome) | ||
I(1,4,5)P3 | Arrow | R-HSA-169683 (Reactome) | ||
I(1,4,5)P3 | R-HSA-169680 (Reactome) | |||
IKKA:IKBKB:IKBKG | R-HSA-1168637 (Reactome) | |||
IP3 receptor homotetramer | R-HSA-169680 (Reactome) | |||
ITPR:I(1,4,5)P3 tetramer | Arrow | R-HSA-169680 (Reactome) | ||
ITPR:I(1,4,5)P3 tetramer | mim-catalysis | R-HSA-1168376 (Reactome) | ||
ITPR:I(1,4,5)P3 tetramer | mim-catalysis | R-HSA-169683 (Reactome) | ||
LYN | mim-catalysis | R-HSA-983709 (Reactome) | ||
MALT1 | R-HSA-1168644 (Reactome) | |||
MAP3K7 | R-HSA-1168637 (Reactome) | |||
NCK1 | R-HSA-983704 (Reactome) | |||
NF-kappa-B p50,p65,c-Rel:IKB | R-HSA-1168638 (Reactome) | |||
NF-kappa-B p50,p65,c-Rel:p-IKB | Arrow | R-HSA-1168638 (Reactome) | ||
NF-kappa-B p50,p65,c-Rel:p-IKB | R-HSA-1168642 (Reactome) | |||
NF-kappaB p50,p65,c-Rel dimer | Arrow | R-HSA-1168633 (Reactome) | ||
NF-kappaB p50,p65,c-Rel dimer | Arrow | R-HSA-1168640 (Reactome) | ||
NF-kappaB p50,p65,c-Rel dimer | R-HSA-1168633 (Reactome) | |||
NF-kappaB p50,p65,c-Rel:ub-p-IKB | Arrow | R-HSA-1168643 (Reactome) | ||
NF-kappaB p50,p65,c-Rel:ub-p-IKB | R-HSA-1168640 (Reactome) | |||
NF-kappaB:p-IkB:SCF-betaTrCP | Arrow | R-HSA-1168642 (Reactome) | ||
NF-kappaB:p-IkB:SCF-betaTrCP | R-HSA-1168643 (Reactome) | |||
Orai1 dimer | R-HSA-434700 (Reactome) | |||
PI(3,4,5)P3 | Arrow | R-HSA-2045911 (Reactome) | ||
PI(3,4,5)P3 | Arrow | R-HSA-2076220 (Reactome) | ||
PI(4,5)P2 | R-HSA-1112666 (Reactome) | |||
PI(4,5)P2 | R-HSA-2045911 (Reactome) | |||
PI(4,5)P2 | R-HSA-2076220 (Reactome) | |||
PI(4,5)P2 | R-HSA-983704 (Reactome) | |||
PIK3AP1 | R-HSA-983704 (Reactome) | |||
PIK3CD:PIK3R1 | R-HSA-983704 (Reactome) | |||
PIK3CD:PIK3R1 | mim-catalysis | R-HSA-983704 (Reactome) | ||
PLC gamma1,2 | R-HSA-983704 (Reactome) | |||
PRKCB | R-HSA-1168373 (Reactome) | |||
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCR | TBar | R-HSA-983707 (Reactome) | ||
PTPN6:p-Y762,807,822-CD22:Antigen:p-BCR | TBar | R-HSA-983709 (Reactome) | ||
Phosphatidylserine | R-HSA-1168373 (Reactome) | |||
Phosphorylated NFATC1,2,3 | R-HSA-2025890 (Reactome) | |||
R-HSA-1112666 (Reactome) | Phospholipase C gamma (PLC-gamma) is activated by phosphorylation in response to antigen-binding by the B cell receptor (Carter et al. 1991, Roitman and Wang 1992, Rodriguez et al. 2001, Kim et al. 2004, Sekiya et al. 2004). Phospholipase C gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate and diacylglycerol (Carter et al. 1991, Kim et al. 2004). Human B cells contain both PLC-gamma1 and PLC-gamma2, with PLC-gamma2 predominating (Coggeshall et al. 1992). | |||
R-HSA-1168373 (Reactome) | Human Protein kinase C beta (PKC-beta) is activated by calcium ions, diacylglycerol, and binds phosphatidylserine (Kochs et al. 1991). Experiments in mice have shown that knocking out PKC-beta causes severe defects in B cells, leading to the conclusion that PKC-beta is the predominant signaling PKC in these cells (Leitges et al. 1996, Su et al. 2002, Saijo et al. 2002). | |||
R-HSA-1168374 (Reactome) | RasGRP1 and RasGRP3 translocate to the plasma membrane where they bind diacylglycerol (Lorenzo et al. 2001) and are phosphorylated (Teixeira et al. 2003, Zheng et al. 2005). Though RasGRP3 is phosphorylated in vitro and in some cell lines (e.g. Ramos cells) by protein kinase C theta (PKC-theta, Zheng et al. 2005), normal B cells do not contain PKC-theta (Meller et al. 1999). Both Rasgrp1 and Rasgrp3 participate in activating Ras in response to BCR signaling in mouse B cells (Coughlin et al. 2005). | |||
R-HSA-1168376 (Reactome) | In the resting state the luminal domain of STIM1 binds Ca2+ ions within the endoplasmic reticulum and this binding prevents dimerization of STIM1 (Luik et al. 2008). Upon depletion of Ca2+ ions from the endoplasmic reticulum, STIM1 is no longer bound to Ca2+ and forms homodimers (Muik et al. 2008, Luik et al. 2008, Park et al. 2009). | |||
R-HSA-1168633 (Reactome) | Nf-kappaB subunits contain nuclear localization sequences and, in the absence of IkB, are translocated to the nucleus (Bauerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008). c-Rel binds to importins alpha5, alpha6, and alpha7; RelB binds to importins alpha5 and alpha6; p52 binds importin alpha3, alpha4, alpha5, and alpha6 (Fagerlund et al. 2008) | |||
R-HSA-1168635 (Reactome) | CARMA1 is phosphorylated at serines 559, 644, and 652 by Protein Kinase C beta (PKC-beta) (Sommer et al. 2005). CARMA1 is constitutively oligomerized (Tanner et al. 2007) and most CARMA1 in unstimulated cells is cytosolic (Sommer et al. 2005, Tanner et al. 2007), though a portion is constitutively associated with the plasma membrane (Gaide et al. 2002, Sommer et al. 2005). After phosphorylation, CARMA1 is associated with lipid rafts in the plasma membrane (Sommer et al. 2005). Note that some publications refer to CARMA1 with a different N-terminal methionine that is 7 amino acids shorter. In this case the phosphorylated serines are 552, 537, and 645. | |||
R-HSA-1168636 (Reactome) | RasGRP1 (Roose et al. 2007) and RasGRP3 (Ohba et al. 2000, Yamashita et al. 2000, Rebhun et al. 2000, Lorenzo et al. 2001) catalyze the exchange of GDP for GTP bound by RAS. | |||
R-HSA-1168637 (Reactome) | TAK1 and the IKK complex are observed to migrate from the cytosol to lipid rafts containing the CARMA1:BCL10:MALT1 (CBM) complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). By analogy with activation of NF-KappaB signaling in T cells, TAK1 in B cells may also be bound to TAB1 and TAB2 or TAB3, which bind K63-conjugated polyubiquitin on a TRAF protein bound to the CBM complex (reviewed in Shinohara et al. 2009). | |||
R-HSA-1168638 (Reactome) | Activated IKK complex phosphorylates the I-kappaB component of the cytoplasmic NF-kappaB complex (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999). B cells contain I-kappaB-alpha, I-kappaB-beta, and I-kappaB-epsilon (Whiteside et al. 1997, Li and Nabel 1997). | |||
R-HSA-1168640 (Reactome) | Phosphorylated, ubiquitinated IkB is degraded by the proteasome (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). IkB does not dissociate from NF-kB before it is proteolyzed (Miyamoto et al. 1994, Traenckner et al. 1994, DiDonato et al. 1995, Lin et al. 1995). | |||
R-HSA-1168641 (Reactome) | TAK1 phosphorylates IKK-beta (Wang et al. 2001). As inferred from chicken B cells, the reaction in human B cells may occur when TAK1 and the IKK complex are associated with the CARMA1:BCL10:MALT1 (CBM) complex. During T cell activation TAK1 forms a complex with TAB1 and TAB2, which binds K-63 conjugated polyubiquitin attached to TRAF6 associated with the CBM complex (Sun et al. 2004, reviewed in Shinohara et al. 2009). TRAF6 also polyubiquitinates IKK-gamma in T cells (Zhou et al. 2004). B cells contain functional TRAF6 and TRAF2 (Zhang et al. 2010) so the same mechanism may occur during activation of B cells. | |||
R-HSA-1168642 (Reactome) | SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) bind IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999). | |||
R-HSA-1168643 (Reactome) | SKP:Cul:F-box (SCF) complexes containing F-box factors Beta-TrCP1 (BTRCP, E3RSIkappaB) or beta-TrCP2 (BTRCP2, FBXW11, HOS) catalyze the polyubiquitination of IkappaB (Yaron et al. 1998, Fuchs et al. 1999, Suzuki et al. 1999, Tan et al. 1999, Winston et al. 1999, Wu and Ghosh 1999). | |||
R-HSA-1168644 (Reactome) | CARMA1 is phosphorylated and recruits BCL10 and MALT1 to the plasma membrane to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007). Evidence from T cells (Jurkat cells) indicates that MALT1 and BCL10 oligomerize to activate the IKK complex (Zhou 2004). | |||
R-HSA-169680 (Reactome) | The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening. | |||
R-HSA-169683 (Reactome) | IP3 promotes the release of intracellular calcium. | |||
R-HSA-2025882 (Reactome) | As inferred from mouse (Okamura et al. 2000), calcineurin dephosphorylates NFATC2 at 13 serine residues (Batiuk et al. 1997, Kim et al. 2000). B lymphocytes also contain NFATC2 and NFATC3 which are inferred to undergo dephosphorylation at homologous serines. Dephosphorylation of NFATs exposes a nuclear localization signal which cause NFATs to be imported into the nucleus (Kim et al. 2000). In mouse, Calcineurin is observed to also transit into the nucleus in a complex with NFATs and may remain associated (Shibasaki et al. 1996). | |||
R-HSA-2025890 (Reactome) | Calcium activates calcineurin in two ways: binding the regulatory subunit of calcineurin directly and binding calmodulin which then interacts with the catalytic subunit of calcineurin. As inferred from mouse, B lymphocytes contain the R1 regulatory subunit (PPP3R1) and the beta catalytic subunit (PPP3CB). In the presence of calcium and calcium:calmodulin calcineurin binds phosphorylated and unphosphorylated NFATs at 2 regions in the N-terminus (Luo et al. 1996, Garcia-Cozar et al. 1998, Park et al. 2000, evidence from mouse in Loh et al. 1996 and Wesselborg et al. 1996). Calcineurin also weakly interacts with NFATs in the absence of calcium (Garcia-Cozar et al. 1998). | |||
R-HSA-2045911 (Reactome) | PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992, Chantry et al. 1997). Experiments in mice indicate that PI3K associated with BCAP is partly responsible for the activity (Aiba et al. 2008). (PI3K associated with CD19 is also partly responsible (Aiba et al. 2008).) | |||
R-HSA-2076220 (Reactome) | PI3K generates phosphoinositol-3,4,5-trisphosphate (PIP3) from PIP2 after activation of the BCR (Gold et al. 1992). Experiments in mice indicate that PI3K associated with CD19 is partly responsible for the activity (Buhl et al. 1997, Otero et al. 2001, Aiba et al. 2008). (PI3K associated with BCAP is also partly responsible (Aiba et al. 2008).) | |||
R-HSA-2089927 (Reactome) | The polybasic region of STIM1 interacts with 2 aspartate residues in the C-terminal region of TRPC1 (Zeng et al. 2008, Huang et al. 2006). The STIM1:TRPC1 complex can form a tenary complex with ORAI1 (Ong et al. 2007, Jardin et al. 2008) and ORAI participates in function of STIM1:TRPC1 channels (Cheng et al. 2008, Cheng et al. 2011). As inferred from chicken DT40 cells, TRPC1 (and possibly other TRP channels) participates in store-operated calcium influx during signaling by the B cell receptor (Mori et al. 2002). | |||
R-HSA-2089943 (Reactome) | TRPC1 forms a channel that transports Ca2+ across the plasma membrane. TRPC1 is gated by STIM1 (Ong et al. 2007). | |||
R-HSA-434700 (Reactome) | Sustained calcium signalling in lymphocytes and platelets requires the uptake of extracellular calcium when intracellular stores are depleted. The process whereby intracellular calcium depletion stimulates calcium uptake is often referred to as Store-operated calcium entry (SOCE). Store depletion is sensed by stromal interaction molecule 1 (STIM1), which then translocates to the plasma membrane and associates with 2 dimers of Orai1 to form a calcium-release activated calcium (CRAC) channel. | |||
R-HSA-434798 (Reactome) | Activation of Calcium-release-activated (CRAC) channels allows influx of calcium. The Orai component of CRAC is responsible for the selectivity of the channel, while the Stim component is responsible for activation. | |||
R-HSA-74448 (Reactome) | Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions. | |||
R-HSA-983696 (Reactome) | Mature, unstimulated B cells express IgM and IgD immunoglobulins on their surfaces (Fu et al. 1974, Fu et al. 1975, reviewed in Kunkel 1975). The immunoglobulins form B cell receptor (BCR) complexes with disulfide-linked heterodimers of Ig-alpha (CD79A) and Ig-beta (CD79B), which have cytoplasmic tails containing immunoreceptor tyrosine-based activation motifs (ITAMs) (van Noesel et al. 1992, Saouaf et al. 1995, inferred from mouse Hombach et al. 1990, Wienands et al. 1990). Upon binding of antigen to the immunoglobulin a chain of phosphorylation events is triggered (Nel et al. 1984, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Harwood and Batista 2010). | |||
R-HSA-983700 (Reactome) | The SYK protein tyrosine kinase binds specifically to phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Law et al. 1994, Saouaf et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding activates the kinase activity of SYK (Rowley et al. 1995, Tsang et al. 2008). | |||
R-HSA-983703 (Reactome) | BLNK (SLP-65, BASH) forms a stable complex with GRB2, SOS1, and CIN85 in the cytosol. The complex is recruited to the plasma membrane where activated (phosphorylated) SYK phosphorylates BLNK at tyrosines 72, 84, 96, 178, and 189 (Fu et al. 1998, Chiu et al. 2002, inferred from mouse in Wienands et al. 1998, from chicken in Oellerich et al. 2009). Phosphorylated BLNK serves as a scaffold that binds effector molecules such as Phospholipase C. As inferred from mouse, BLNK interacts with phosphorylated tyrosines on CD79A (Ig-alpha) (Engels et al. 2001, Kabak et al. 2002). | |||
R-HSA-983704 (Reactome) | Phosphorylated SYK phosphorylates BLNK (SLP-65, Fu et al. 1998, Chiu et al. 2002) and BCAP (inferred from mouse, Okada et al. 2000). Effector molecules are then recruited: phosphoinositol 3-kinase (PI3K), Phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases. As inferred from chicken DT40 cells and mouse B cells (Okada et al. 2000), phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates Phospholipase C gamma-2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002). SYK phosphorylates SHC which then binds GRB2 (Saxton et al. 1994, Harmer and DeFranco 1997). CD19 in a stable complex with VAV1 is phosphorylated by Src kinases (inferred from mouse, Xu et al. 2002) and possibly by LYN (inferred from mouse, Fujimoto et al. 2000) in response to BCR activation. Phosphorylated CD19 then binds PI3K (Roifman and Ke 1993, Chalupny et al. 1993, Uckun et al. 1993, Weng et al. 1994, Brooks et al. 2000, Brooks et al. 2004) and can bind PLC-gamma2, which competes with VAV1 for the same binding site on CD19 (Brooks et al. 2000, Brooks et al. 2004). | |||
R-HSA-983707 (Reactome) | The SYK protein tyrosine kinase autophosphorylates at tyrosines 131, 323, 348, 352, 525, and 526 (Law et al. 1994, Rowley et al. 1995, Baldock et al. 2000, Irish et al. 2006, Papp et al. 2007, Chen et al. 2008, Tsang et al. 2008). The autophosphorylation increases the kinase activity of SYK. SYK is also phosporylated on additional residues in response to BCR activation (Bohnenberger et al. 2011). | |||
R-HSA-983709 (Reactome) | The B cell receptor (BCR) comprises an immunoglobulin complexed with a heterodimer of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29). After immunoglobulin IgM or IgD binds antigen the associated Ig-alpha and Ig-beta are each observed to be phosphorylated at two tyrosine residues in the cytoplasmic immunoreceptor tyrosine-activated motif (ITAM) (Sanchez et al. 1993, Hata et al. 1994, Saouaf et al. 1994, Saouaf et al. 1995). Saouaf et al. (1995) showed that the kinase Blk could phosphorylate both tyrosines of each ITAM and that the kinase SYK specifically bound phosphorylated but not unphosphorylated ITAMs. In mouse the kinase Lyn and other kinases phosphorylate one tyrosine and Syk is believed to phosphorylate the other (Yamanashi et al. 1991, Flaswinkel and Reth 1994, Rolli et al. 2002). | |||
RASGRP1,3 | R-HSA-1168374 (Reactome) | |||
SCF-beta-TrCp1,2 | Arrow | R-HSA-1168643 (Reactome) | ||
SCF-beta-TrCp1,2 | R-HSA-1168642 (Reactome) | |||
SHC1 p46,p52 | R-HSA-983704 (Reactome) | |||
STIM1 Dimer | Arrow | R-HSA-1168376 (Reactome) | ||
STIM1 Dimer | R-HSA-2089927 (Reactome) | |||
STIM1 Dimer | R-HSA-434700 (Reactome) | |||
STIM1:Calcium | R-HSA-1168376 (Reactome) | |||
STIM1:TRPC1 | Arrow | R-HSA-2089927 (Reactome) | ||
STIM1:TRPC1 | mim-catalysis | R-HSA-2089943 (Reactome) | ||
SYK | R-HSA-983700 (Reactome) | |||
TRPC1 | R-HSA-2089927 (Reactome) | |||
Ub | R-HSA-1168643 (Reactome) | |||
VAV1 | R-HSA-983704 (Reactome) | |||
p-BCL10 | R-HSA-1168644 (Reactome) | |||
p-CARMA1 Oligomer | Arrow | R-HSA-1168635 (Reactome) | ||
p-CARMA1 Oligomer | R-HSA-1168644 (Reactome) | |||
p-RASGRP1,3:DAG | Arrow | R-HSA-1168374 (Reactome) | ||
p-RASGRP1,3:DAG | mim-catalysis | R-HSA-1168636 (Reactome) | ||
p21 RAS:GDP | R-HSA-1168636 (Reactome) | |||
p21 RAS:GTP | Arrow | R-HSA-1168636 (Reactome) |