B cell receptor signaling pathway (WP1025)

Bos taurus

The functional B-cell receptor is a multi-protein complex consisting of an antigen binding subunit and a signaling subunit. The antigen binding subunit is the membrane bound immunoglobulin and the signaling subunit consists of the Igα and Igβ proteins, which are covalently bound to each other. Both Igα and Igβ proteins have an immunoreceptor tyrosine -based activation motif (ITAM) each in its cytoplasmic region, which is responsible for the initiation and propagation of signaling. Antigen binding to the immunoglubulin results in the aggregation of both the immunoglobulin and the Igα/β subunits. This results in the phosphorylation of the tyrosine residues in the ITAM motif of the Igα/β subunits by the src-family of protein tyrosine kinases Lyn and Syk. The Src family kinases are initially in the proximity of the BCR as a result of membrane anchoring by virtue of its their acetylation. The N-terminal region of the kinases can also interact with the non-phosphorylated ITAMs of Igα. This association is further enhanced upon BCR engagement as a result of accumulation in BCR containing lipid rafts and SH2 domain mediated binding to the phosphorylated tyrosine residues in ITAMs. This increased association helps in amplifying the BCR mediated signaling. Doubly phosphorylated Igα/β ITAMs are necessary for efficient recruitment of Syk and its activation. Activated Syk then phsophorylates the adapter molecule B cell linker protein (BLNK), which acts as molecular scaffold for the recruitment of multiple effectors and hence the propagation of multiple signaling pathways. BLNK binds to Btk and PLCγ2 which results in optimal phosphorylation and activation of PLC. This is an important mechanism which links BCR to Ca2+ signaling. Apart from the PLC mediated Ca2+ signaling, BCR triggering also results in the the activaion of phosphatidylinositol-3 kinase (PI-3K). This activation takes place through the recruitment of p85 adaptor subunit of PI-3K to CD19 co-receptor, which is phosphorylated by Lyn on its cytoplasmic Y-X-X-M motif. Alternatively, PI-3K can be recruited to the plasma membrane by other adapter molecules including PIK3AP, CBL or GAB1/2. PI-3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidyl inositol 3,4,5-bisphosphate. Akt, a serine threonine kinase, is recruited to the plasma membrane by virtue of its N-terminal PH-domain where it is activated by conformational changes and phosphorylation. Activated Akt phosphorylates several substrates resulting in diverse physiological consequences: Forkhead transcription factors - resulting in its degradation and hence inhibition of expression of pro-apoptotic genes, glycogen synthase kinase-3 GSK3 -leading to its inhibition and hence regulation of cell-cycle. The tanscription factor NF-kappaB is also found to be activated in BCR signaling in a Btk, PI-3K and PKC dependent manner. BCR engagement can also result in the association of GRB2/SOS complex with either SHC or BLNK, which results in the activation of the Ras/Raf/MEK/ERK signaling cascade. This cascade leads to the activation of transcription factors including ELK and MYC. BCR activation also results in the activation of JNKs and p38MAPK. Please access this pathway at [http://www.netpath.org/netslim/bcr_pathway.html NetSlim] database. If you use this pathway, please cite the following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.

Authors

Alex Pico , Christine Chichester , Martina Summer-Kutmon , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Cell Type Ontology

B cell

Pathway Ontology

signaling pathway pertinent to immunity B cell receptor signaling pathway

Participants

Label Type Compact URI Comment
CHUK Protein ensembl:ENSBTAG00000007591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
IKBKG Protein ensembl:ENSBTAG00000006268 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
REL Protein ensembl:ENSBTAG00000015386 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
RELA Protein ensembl:ENSBTAG00000013895 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RAF1 Protein ensembl:ENSBTAG00000045748 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
MAP3K7 Protein ensembl:ENSBTAG00000002625 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
HRAS Protein ensembl:ENSBTAG00000046644 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
CREB1 Protein ensembl:ENSBTAG00000005474 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1385
RAC2 Protein ensembl:ENSBTAG00000011043 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5880
HCLS1 Protein ensembl:ENSBTAG00000001009 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3059
CAMK2A Protein ensembl:ENSBTAG00000020087 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:815
TIEG2 Protein ensembl:ENSBTAG00000046218 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8462
SH3BP2 Protein ensembl:ENSBTAG00000013996 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6452
MAP2K6 Protein ensembl:ENSBTAG00000001609 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5608
VAV2 Protein ensembl:ENSBTAG00000004511 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7410
RASGRP3 Protein ensembl:ENSBTAG00000008006 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:25780
NFATC2 Protein ensembl:ENSBTAG00000018270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4773
PRKCD Protein ensembl:ENSBTAG00000008719 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5580
BCL6 Protein ensembl:ENSBTAG00000001511 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:604
NCK1 Protein ensembl:ENSBTAG00000018427 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4690
INPP5D Protein ensembl:ENSBTAG00000020173 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3635
GRB2 Protein ensembl:ENSBTAG00000004736 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
VAV1 Protein ensembl:ENSBTAG00000039160 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7409
RPS6KA1 Protein ensembl:ENSBTAG00000014447 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6195
MYC Protein ensembl:ENSBTAG00000008409 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4609
MALT1 Protein ensembl:ENSBTAG00000027916 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10892
CD79B Protein ensembl:ENSBTAG00000044204 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:974
NFATC3 Protein ensembl:ENSBTAG00000004368 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4775
SYK Protein ensembl:ENSBTAG00000004767 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6850
BRAF Protein ensembl:ENSBTAG00000021761 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:673
CRK Protein ensembl:ENSBTAG00000005665 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1398
PLCG1 Protein ensembl:ENSBTAG00000017584 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
SHC1 Protein ensembl:ENSBTAG00000019838 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6464
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
PTPRC Protein ensembl:ENSBTAG00000023144 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5788
FOXO1 Protein ensembl:ENSBTAG00000044105 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2308
ELK1 Protein ensembl:ENSBTAG00000015817 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2002
PTPN6 Protein ensembl:ENSBTAG00000020294 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5777
PIK3R1 Protein ensembl:ENSBTAG00000010989 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
PTPN11 Protein ensembl:ENSBTAG00000002048 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5781
MAPK4 Protein ensembl:ENSBTAG00000009907 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5596
PIK3CG Protein ensembl:ENSBTAG00000020848 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5294
PLCG2 Protein ensembl:ENSBTAG00000002103 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5336
GAB1 Protein ensembl:ENSBTAG00000002813 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2549
MAPK14 Protein ensembl:ENSBTAG00000020783 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAP2K2 Protein ensembl:ENSBTAG00000024450 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5605
LYN Protein ensembl:ENSBTAG00000020034 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4067
PIK3AP1 Protein ensembl:ENSBTAG00000019872 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:118788
ETS1 Protein ensembl:ENSBTAG00000002341 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2113
CD79A Protein ensembl:ENSBTAG00000001882 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:973
GSK3A Protein ensembl:ENSBTAG00000020756 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2931
CD19 Protein ensembl:ENSBTAG00000032122 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:930
LAT2 Protein ensembl:ENSBTAG00000045767 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7462
RAC1 Protein ensembl:ENSBTAG00000009233 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RAPGEF1 Protein ensembl:ENSBTAG00000020791 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2889
CD81 Protein ensembl:ENSBTAG00000047495 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:975
GSK3B Protein ensembl:ENSBTAG00000048057 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
MAX Protein ensembl:ENSBTAG00000017994 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4149
BTK Protein ensembl:ENSBTAG00000019250 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:695
CDC42 Protein ensembl:ENSBTAG00000001700 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
CBL Protein ensembl:ENSBTAG00000006817 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:867
MAPK8 Protein ensembl:ENSBTAG00000007876 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9 Protein ensembl:ENSBTAG00000004709 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
BLNK Protein ensembl:ENSBTAG00000021358 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:29760
BLK Protein ensembl:ENSBTAG00000005049 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:640
PIP5K1A Protein ensembl:ENSBTAG00000006099 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8394
PDPK1 Protein ensembl:ENSBTAG00000034436 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5170
TEC Protein ensembl:ENSBTAG00000005062 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7006
CRKL Protein ensembl:ENSBTAG00000045548 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1399
PTPN18 Protein ensembl:ENSBTAG00000011658 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:26469
LCK Protein ensembl:ENSBTAG00000012695 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3932
MAP2K1 Protein ensembl:ENSBTAG00000033983 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
FYN Protein ensembl:ENSBTAG00000011851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2534
MAPK1 Protein ensembl:ENSBTAG00000010312 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
JUN Protein ensembl:ENSBTAG00000004037 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
PIP5K1C Protein ensembl:ENSBTAG00000000710 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23396
PIP5K1B Protein ensembl:ENSBTAG00000009917 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8395
PRKCB Protein ensembl:ENSBTAG00000020921 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5579
BCL10 Protein ensembl:ENSBTAG00000013851 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8915
CARD11 Protein ensembl:ENSBTAG00000014698 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84433
IKBKB Protein ensembl:ENSBTAG00000007599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
GTF2I Protein ensembl:ENSBTAG00000009780 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2969
BIKBA Protein ensembl:ENSBTAG00000016683 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
CD22 Protein ensembl:ENSBTAG00000011887 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:933
ATF2 Protein ensembl:ENSBTAG00000002295 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1386
SOS1 Protein ensembl:ENSBTAG00000011643 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
DAPP1 Protein ensembl:ENSBTAG00000007921 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:27071
MAP4K1 Protein ensembl:ENSBTAG00000021145 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11184

References

  1. NetPath: a public resource of curated signal transduction pathways. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia