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. <i>Genome Biology</i>. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP23 CPTAC Assay Portal] a83 BCR engagement can result in tyrosine phosphorylation Syk at position 352 and 759 in human primary B-cells, CLL B-cells and DLBCL as well as mouse B-cells. ERK1 is phosphorylated upon BCR engagement in human CCL B-cells, Ramos cells as well as murine WEHI-231 cells, A20 cells, T1 B-cells, follicular B-cells, bone marrow and splenic B-cells. p38 MAPK is phosphorylated upon BCR engagement in murine T1 B-cells, follicular B-cells, splenic B-cells, A20 cells and WEHI-231 cells. JNK1 is phosphorylated upon BCR engagement in human Ramos cells as well as murine T1 B-cells, follicular B-cells, splenic B-cells and WEHI-231 cells. JNK2 is phosphorylated upon BCR engagement in murine A20 cells, T1 B-cells, follicular B-cells, splenic B-cells and WEHI-231 cells. ERK2 is phosphorylated upon BCR engagement in human CCL B-cells, Ramos cells as well as murine WEHI-231 cells, A20 cells, T1 B-cells, follicular B-cells, splenic B cells and bone marrow B-cells. NFKBIA is phosphorylated upon BCR engagement in murine T1 B-cells, follicular and splenic B-cells. BCR stimulation induces the upregulation of ILF2 through ERK pathway RPS6KA1 phosphorylates CREB1 at the Ser133 site upon BCR stimulation in Bal17 B cells. BCR stimulation leads to the association of SHC1 to tyrosine phosphorylated C-terminal of CD22 in murine K46 and BAL17IgM cells. Upon BCR activation, SH3 domain of Crk bind C3G in RAMOS human B lymphoma cells. Phosphorylation of CD79B by SYK. 3BP2 is tyrosine phosphorylated by Fyn following BCR aggregation on B lymphoma cells. BCR activation induces the tyrosine phosphorylation of SH3BP2 (adaptor 3BP2) and Vav1 and enhanced Vav1 interaction with PRI domain of SH3BP2 in Daudi B cells. BCR stimulation leads to the association of SH3BP2 SH2 domain with Syk in Daudi B cells.3BP2 is a substrate of the protein-tyrosine kinase Syk, which phosphorylates it on Tyr174, Tyr183, and Tyr446. BCR stimulation leads to the association of Bam32 with HPK1 in splenic B cells. BCR stimulation leads to CD19 association with Plcg2 in Daudi cells. B cell receptor activation leads to the interaction of tyrosine phosphorylated CD19 with p85 subunits of PI3-kinase in Daudi B cells. Upon BCR stimulation, tyrosine phosphorylated CD22 binds and activates SHP-1 in B cells. BCR stimulation leads to tyrosine phosphorylation of MAP4K1 and its interaction to SH2 domain of BLNK in Murine WEHI231 B cells. B cell receptor activation induces tyrosine phosphorylation of Gab1 and its interaction with p85 subunits of PI3-kinase via its SH2 domain in Ramos B cells. BCR stimulation leads to rapid tyrosine phosphorylation of Lat2 and its interaction with cytoplasmic signaling molecule Grb2 in Ramos and THP-1 cells. BCR stimulation leads to the association of Rapgef1 with CRKL in RAMOS B cells. B cell receptor activation leads to the interaction of SH2 domain of Fyn with phosphorylated CD79A in B cells and J558L3 cells. Upon stimulation of BCR receptor, LYN phosphorylates BTK at Tyr551 site in Ramos B and NIH 3T3 cells. B cell receptor activation leads to the interaction of SH2 domain of Plcg2 with Blnk in DT40 B cells and the interaction is dependent on the phosphorylation of Tyr189 of BLNK. B cell receptor activation leads to the interaction of Blk with heterodimeric complex of CD79A and CD79B in J558L3 cells and COS cells. B cell receptor activation induces tyrosine phosphorylation of Gab1 and its interaction with PTPN11 in Ramos B cells. Upon stimulation of BCR, SYK phosphorylates SHC1 at the Tyr349, Tyr427 site in Bal-17 B cells. BTK phosphorylates PIK3AP1 upon BCR stimulation in mouse splenic B cells. upon BCR ligation GAB2,p85 subunit of PI3K and SHP2 form a complex in murine 38c13 cells. TEC phosphorylates PLCG2 at the Tyr753, Tyr759 site upon BCR stimulation in XLA-1 B cells. BCR activation induces the dephosphorylation of TEC by PTPN18 in COS7 cells. phosphorylated MAPK4 binds to Gab1 in BCR stimulated mature B cells. Upon activation of BCR, Cbl is phosphorylated and binds to the SH2 domain of Crk in Ramos B cells. upon BCR ligation Syk phosphorylates GAB2 in murine A20 cells and splenic B-cells. Ligand activated BCR induces the interaction of CD79A with Lck. MAPK8 phosphorylates JUN upon BCR stimulation in DT40 cells. AKT1 phosphorylates FOXO1 at the Thr24 site upon BCR stimulation in A20 cells. B cell receptor activation leads to the interaction of extracellular part of CD19 with CR2 in Daudi B cells. BCR activation induces association and phosphorylation of CD79A by LYN in B cells PDPK1 phosphorylates AKT1 at the Ser473 site upon stimulation of BCR in murine splenic B cells. BCR activation induces the phosphorylatin of PTPN18 by TEC in COS7 cells. BTK associates with PIP5K's upon BCR activation in BCR stimulated Ramos, A20 and primary splenic B cells. PRKCB1 phosphorylates CHUK upon BCR stimulation in murine splenic B cells. PRKCB1 phosphorylates IKBKB upon BCR stimulation in murine splenic B cells. Upon BCR stimulation, SYK phosphorylates BLNK at the Tyr72, Tyr84, Tyr96 site in Daudi cells MAPK1 phosphorylates ELK1 upon BCR stimulation in DT40 cells. BCR activation induces the phosphorylation of MAX by MAPK14 B cell activation induces the phosphorylation of ETS1. Upon BCR stimulation BAP135 is associated with PH domain of BTK in Ramos and 293 cells. BCCR activation induces the phosphorylation of HCLS1 by LYN in M1 cells. B cell receptor activation leads to the interaction of extracellular part of CD19 with CD81 in Daudi B cells. BCR stimulation induced SYK mediated HCLS1 tyrosine phosphorylation in WEHI-231 cells. BCR stimulation induces the upregulation of MEF2D BCR stimulation induces the upregulation of IRF4 through NFAT pathway BCR stimulation leads to the upregulation of E2F3 through NFKB pathway. B cell receptor stimulation induced the autophosphorylation of LYN in BAL-17 cells. B cell receptor stimulation induced the autophosphorylation of SYk in B cells. B cell receptor stimulation induced the autophosphorylation of BTK in NIH 3T3 cells. B cell receptor stimulation induced the autophosphorylation of TEC in Ramos cells. 20067622 PubMed NetPath: a public resource of curated signal transduction pathways. Genome Biol 2010 Kandasamy K Mohan SS Raju R Keerthikumar S Kumar GS Venugopal AK Telikicherla D Navarro JD Mathivanan S Pecquet C Gollapudi SK Tattikota SG Mohan S Padhukasahasram H Subbannayya Y Goel R Jacob HK Zhong J Sekhar R Nanjappa V Balakrishnan L Subbaiah R Ramachandra YL Rahiman BA Prasad TS Lin JX Houtman JC Desiderio S Renauld JC Constantinescu SN Ohara O Hirano T Kubo M Singh S Khatri P Draghici S Bader GD Sander C Leonard WJ Pandey A signaling pathway pertinent to immunity PW:0000818 Pathway Ontology B cell CL:0000236 Cell Type B cell receptor signaling pathway PW:0000822 Pathway Ontology