Immune response - BCR pathway

BCR signaling pathway

The BCR (B-Cell antigen Receptor) plays a critical role in development, survival, and activation of B lymphocytes. The BCR is composed of membrane immunoglobulin (IgM) molecules associated with CD79a molecule, immunoglobulin-associated alpha - CD79b molecule, immunoglobulin-associated beta heterodimers (CD79 complex) [1]. The IgM subunits bind antigens and cause receptor aggregation, while the CD79 complex subunits transduce intracellular signaling cascades. Upon activation, BCRs activate the Spleen tyrosine kinase (Syk) and v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn), which phosphorylate and activate Phospholipases C, gamma (PLC-gamma), and Bruton agammaglobulinemia tyrosine kinase (BTK), respectively. BTK also activates both PLC-gamma isoforms [2], [3].

Once activated, these tyrosine kinases phosphorylate activate several signaling pathways, including Ras-ERK and PLC-gamma signal cascades, which lead to the activation of transcription factors, such as ELK1, member of ETS oncogene family (ELK1), Early growth response 1 (EGR1), Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 (NF-AT1(NFATC2)) and Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB), and inhibit transcription factors, such as B-cell CLL/lymphoma 6 (Bcl-6).

PLC-gamma activation that is mediated by BTK and B-cell linker (BLNK), leads to the conversion of phosphatidylinositol-4,5-biphosphate (PtdIns(4,5)P2) to the second messengers inositol-1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). IP3 binds to Inositol 1,4,5-triphosphate receptor (IP3 Receptor), which is localized primarily on the endoplasmic reticulum and stimulates the release of calcium from intracellular stores. Calcium-bound Calmodulin 2 (Calmodulin) associates with and activates Protein phosphatase 3, catalytic subunit (Calcineurin A (catalytic)). Calcineurin A (catalytic) dephosphorylates NF-AT1(NFATC2) leading to theirs translocation to the nucleus [4].

DAG activates Protein kinase C, beta (PKC-beta). PKC-beta in particular, is a critical component of the BCR signalosome, and is essential for recruitment and activation of the IKK complex resulting in the translocation of NF-kB to the nucleus [5].

Several transmembrane receptors are known to modulate specific elements of BCR signaling. These include Protein tyrosine phosphatase, receptor type, C (CD45) and Fc fragment of IgG, low affinity IIb, receptor (Fc gamma RII beta).CD45 has its own protein tyrosine phosphatase activity and inhibits v-yes-1 Yamaguchi sarcoma viral related oncogene homolog (Lyn) activity by dephosphorylation leading to reduction in CD45's negative regulatory effects [6], [7].

Lyn phosphorylates and activates co-receptor CD19 molecule (CD19) and receptor Fc-gamma-RII [8], [9]. CD19 is a cell surface molecule, which assembles with the antigen receptor of B lymphocytes in order to decrease the threshold for antigen receptor-dependent stimulation. This co-receptor complex is composed of CD19, Complement component receptor 2 (CD21) and CD81 molecule (CD81) [10]. CD21 binds to opsinized antigenic particles and is primarily responsible for signal transduction. Phosphorylation of CD19 by Lyn generates binding sites for Phosphoinositide-3-kinase, catalytic (PI3K cat class IA). PI3K cat class IA activates Phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) and Vav 1 and 2 guanine nucleotide exchange factors (VAV-1 and VAV-2). The CD19 co-receptor physically interacts with VAV-1 and VAV-2 and synergistically enhances their phosphorylation induced by the BCR. VAV-1 and VAV-2 activate small GTP binding proteins Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (CDC42) [11].

PtdIns(3,4,5)P3 associates with the inner phospholipid bilayer of the plasma membrane to promote the recruitment of pleckstrin homology (PH) domain-rich proteins such as 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)) and V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)). PDK (PDPK1) activates AKT(PKB), which phosphorylates downstream target including BCL2 Antagonist of Cell Death (BAD), Glycogen synthase kinase 3 beta (GSK3 beta) and Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (P70 S6 kinase1), thereby regulating apoptosis, cell cycle, cell growth and other cellular processes [12].

Fc-gamma-RII activates the Inositol polyphosphate-5-phosphatase, 145kDa (SHIP). SHIP converts PtdIns(3,4,5)P3 into PtdIns (3,4)P2, which is the second messenger that activates PDK (PDPK1) and AKT(PKB) [13].

Lyn also participates in the negative regulation of BCR signaling. Lyn phosphorylates CD22 molecule (CD22), which binds to the Protein tyrosine phosphatase, non-receptor type 6 (SHP-1) and induces Lyn dephosphorylation by SHP-1, thereby down-regulating Btk-dependent IP3 production and calcium mobilization [14], [15].

References:

1. Geisberger R, Crameri R, Achatz G
   Models of signal transduction through the B-cell antigen receptor. Immunology 2003 Dec;110(4):401-10
2. Pao LI, Cambier JC
   Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. Journal of immunology (Baltimore, Md. : 1950) 1997 Mar 15;158(6):2663-9
3. Mohamed AJ, Nore BF, Christensson B, Smith CI
   Signalling of Bruton's tyrosine kinase, Btk. Scandinavian journal of immunology 1999 Feb;49(2):113-8
4. Hogan PG, Chen L, Nardone J, Rao A
   Transcriptional regulation by calcium, calcineurin, and NFAT. Genes & development 2003 Sep 15;17(18):2205-32
5. Guo B, Su TT, Rawlings DJ
   Protein kinase C family functions in B-cell activation. Current opinion in immunology 2004 Jun;16(3):367-73
6. Harashima A, Suzuki M, Okochi A, Yamamoto M, Matsuo Y, Motoda R, Yoshioka T, Orita K
   CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn. Blood 2002 Dec 15;100(13):4440-5
7. Shrivastava P, Katagiri T, Ogimoto M, Mizuno K, Yakura H
   Dynamic regulation of Src-family kinases by CD45 in B cells. Blood 2004 Feb 15;103(4):1425-32
8. Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, Daeron M
   Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. Journal of immunology (Baltimore, Md. : 1950) 1998 Feb 15;160(4):1647-58
9. Somani AK, Yuen K, Xu F, Zhang J, Branch DR, Siminovitch KA
   The SH2 domain containing tyrosine phosphatase-1 down-regulates activation of Lyn and Lyn-induced tyrosine phosphorylation of the CD19 receptor in B cells. The Journal of biological chemistry 2001 Jan 19;276(3):1938-44
10. Mongini PK, Jackson AE, Tolani S, Fattah RJ, Inman JK
    Role of complement-binding CD21/CD19/CD81 in enhancing human B cell protection from Fas-mediated apoptosis. Journal of immunology (Baltimore, Md. : 1950) 2003 Nov 15;171(10):5244-54
11. O'Rourke LM, Tooze R, Turner M, Sandoval DM, Carter RH, Tybulewicz VL, Fearon DT
    CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav. Immunity 1998 May;8(5):635-45
12. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
13. Lemmon MA
    Phosphoinositide recognition domains. Traffic (Copenhagen, Denmark) 2003 Apr;4(4):201-13
14. Fluckiger AC, Li Z, Kato RM, Wahl MI, Ochs HD, Longnecker R, Kinet JP, Witte ON, Scharenberg AM, Rawlings DJ
    Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation. The EMBO journal 1998 Apr 1;17(7):1973-85
15. Poe JC, Fujimoto Y, Hasegawa M, Haas KM, Miller AS, Sanford IG, Bock CB, Fujimoto M, Tedder TF
    CD22 regulates B lymphocyte function in vivo through both ligand-dependent and ligand-independent mechanisms. Nature immunology 2004 Oct;5(10):1078-87