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) . 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 , .
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
(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 .
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 .
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 , .
Lyn phosphorylates and activates co-receptor CD19
molecule (CD19) and receptor
Fc-gamma-RII , .
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)
. 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
(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
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)
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 .
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
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 , .
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