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].
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Models of signal transduction through the B-cell antigen receptor.
Immunology 2003 Dec;110(4):401-10
- 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
- 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
- Hogan PG, Chen L, Nardone J, Rao A
Transcriptional regulation by calcium, calcineurin, and NFAT.
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Protein kinase C family functions in B-cell activation.
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