B cell receptor signaling pathway (WP23)

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 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. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP23 CPTAC Assay Portal]
last edited

Authors

A.Pandey, MaintBot, Khanspers, Mkutmon, MartijnVanIersel, NetPath, Christine Chichester, Zari, AlexanderPico, L Dupuis, Egonw, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: signaling pathway pertinent to immunity B cell receptor signaling pathway

Cell Type Ontology: B cell

Participants

Label Type Compact Identifier
CHUK Protein ncbigene:1147
IKBKG Protein ncbigene:8517
NFKB1 Protein ncbigene:4790
ILF2 Rna ncbigene:3608
E2F3 Rna ncbigene:1871
REL Protein ncbigene:5966
RELA Protein ncbigene:5970
RAF1 Protein ncbigene:5894
MAP3K7 Protein ncbigene:6885
MEF2D Rna ncbigene:4209
IRF4 Rna ncbigene:3662
HRAS Protein ncbigene:3265
CREB1 Protein ncbigene:1385
MEF2C Rna ncbigene:4208
RAC2 Protein ncbigene:5880
HCLS1 Protein ncbigene:3059
CAMK2A Protein ncbigene:815
BCAR1 Protein ncbigene:8462
RELA Protein ncbigene:5970
SH3BP2 Protein ncbigene:6452
MAP2K6 Protein ncbigene:5608
VAV2 Protein ncbigene:7410
CAMK2A Protein ncbigene:815
RASGRP3 Protein ncbigene:25780
NFATC2 Protein ncbigene:4773
NFATC2 Protein ncbigene:4773
PRKCD Protein ncbigene:5580
BCL6 Protein ncbigene:604
NCK1 Protein ncbigene:4690
INPP5D Protein ncbigene:3635
GRB2 Protein ncbigene:2885
VAV1 Protein ncbigene:7409
RPS6KA1 Protein ncbigene:6195
MYC Protein ncbigene:4609
MALT1 Protein ncbigene:10892
CD79B Protein ncbigene:974
NFATC3 Protein ncbigene:4775
SYK Protein ncbigene:6850
BRAF Protein ncbigene:673
CRK Protein ncbigene:1398
PLCG1 Protein ncbigene:5335
SHC1 Protein ncbigene:6464
AKT1 Protein ncbigene:207
CD45 Protein ncbigene:5788
FOXO1 Protein ncbigene:2308
ELK1 Protein ncbigene:2002
PTPN6 Protein ncbigene:5777
GAB2 Protein ncbigene:9846
PIK3R1 Protein ncbigene:5295
PTPN11 Protein ncbigene:5781
MAPK3 Protein ncbigene:5596
PIK3R1 Protein ncbigene:5295
PIK3R2 Protein ncbigene:5296
PIK3CG Protein ncbigene:5294
PLCG2 Protein ncbigene:5336
GAB1 Protein ncbigene:2549
MAPK14 Protein ncbigene:1432
MAP2K2 Protein ncbigene:5605
LYN Protein ncbigene:4067
PIK3AP1 Protein ncbigene:118788
VAV1 Protein ncbigene:7409
ETS1 Protein ncbigene:2113
CD79A Protein ncbigene:973
GSK3A Protein ncbigene:2931
CD19 Protein ncbigene:930
LAT2 Protein ncbigene:7462
RAC1 Protein ncbigene:5879
RAPGEF1 Protein ncbigene:2889
CD81 Protein ncbigene:975
GSK3B Protein ncbigene:2932
MAX Protein ncbigene:4149
BTK Protein ncbigene:695
CDC42 Protein ncbigene:998
CBL Protein ncbigene:867
PLCG2 Protein ncbigene:5336
PDPK2 Protein ncbigene:653650
MAPK4 Protein ncbigene:5596
MAPK8 Protein ncbigene:5599
MAPK9 Protein ncbigene:5601
BLNK Protein ncbigene:29760
MYC Rna ncbigene:4609
BLK Protein ncbigene:640
RPS6KA1 Protein ncbigene:6195
PIP5K1A Protein ncbigene:8394
PDPK1 Protein ncbigene:5170
TEC Protein ncbigene:7006
CRKL Protein ncbigene:1399
PTPN18 Protein ncbigene:26469
LCK Protein ncbigene:3932
MAP2K1 Protein ncbigene:5604
FYN Protein ncbigene:2534
MAPK1 Protein ncbigene:5594
JUN Protein ncbigene:3725
PIP5K1C Protein ncbigene:23396
PIP5K1B Protein ncbigene:8395
PRKCB1 Protein ncbigene:5579
DAG Protein None
IP3 Protein None
PI-4,5-P2 Protein None
PI-4-P Protein ncbigene:5777
BCL10 Protein ncbigene:8915
CARD11 Protein ncbigene:84433
PTPN6 Protein ncbigene:5777
IKBKB Protein ncbigene:3551
GTF2I Protein ncbigene:2969
NFKBIA Protein ncbigene:4792
MAPK9 Protein ncbigene:5601
CD22 Protein ncbigene:933
ATF2 Protein ncbigene:1386
GRB2 Protein ncbigene:2885
SHC1 Protein ncbigene:6464
SOS1 Protein ncbigene:6654
CR2 Protein ncbigene:1380
DAPP1 Protein ncbigene:27071
MAP4K1 Protein ncbigene:11184
NFATC3 Protein ncbigene:4775
MAPK14 Protein ncbigene:1432
MAPK8 Protein ncbigene:5599
MAPK1 Protein ncbigene:5594
MAPK3 Protein ncbigene:5596
NFKB1 Protein ncbigene:4790
REL Protein ncbigene:5966

References

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