PIP3 signaling in B lymphocytes
B lymphocytes play a critical role in the regulation of numerous cellular processes,
such as proliferation, differentiation, chemotaxis, glucose homeostasis and others. B
cell antigen receptor (BCR) engagement triggers a cascade of biochemical events that
culminate in B cell activation, which entails the proliferation and differentiation of B
The efficient and coordinated generation of a number of second messengers, including
DAG (diacylglycerol), PI(3,4)P2
(phosphatidylinositol-3,4-biphosphate) and PI(3,4,5)P3
(phosphatidylinositol-3,4,5-trisphosphate), is required for normal B cell function.
The BCR is a multiprotein complex that is composed of mIg
molecules (Membrane Immunoglobulin) and associated
heterodimer . The mIg subunits bind antigen and cause receptor
aggregation, while the CD79A/
CD79B subunits transduce signals to the cell interior.
Engagement of receptor activates intracellular protein tyrosine kinases
Syk and Lyn, which
phosphorylate and activate numerous signal proteins, including phosphoinositide-3-kinase
adaptor protein (PI3KAP1) , Bruton tyrosine
kinase (BTK) , and co-receptor
Transmembrane receptor CD45 has its own protein tyrosine
phosphatase activity. CD45 inhibits
Lyn activity by dephosphorylation . BCR
signals somehow reduce CD45's negative regulatory effects by inducing phosphorylation of
CD19 is a cell surface molecule, which assembles with the
BCR in order to decrease the threshold for antigen receptor-dependent
stimulation. Lyn phosphorylates and activates
CD19, which in turn binds to
Vav1 and induces Rac1 signaling
cascade . Rac1 activates phosphatidylinositol
3-kinase class1A via binding to its regulatory subunit (PI3KR
class1A) . CD19 can directly
bind to PI3KR class1A, recruiting PI3K
to the plasma membrane for increasing the specific activity of the enzyme.
Adaptor PI3KAP1 also recruits
PI3K to the plasma membrane .
The class IB of phosphatidylinositol 3-kinase (PI3K class
1B) is activated by G beta/gamma proteins on
stimulation of G protein-coupled receptors (GPCRs).
G beta/gamma proteins mediate membrane recruitment of its
regulatory subunit (PI3KR class 1B), and direct stimulation
of its catalytic subunit (PI3KC class 1B) .
Activated PI3K phosphorylates the membrane lipid phosphatidylinositol 4,5-biphosphate
(PI(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate
PI(3,4,5)P3 is the second messenger that activates
PDK and AKT , .
Phosphatase PTEN acts as a negative regulator for the
PI3K/AKT signaling pathway,
converting PI(3,4,5)P3 into
Upon phosphorylation by
Lyn, Fc-gamma-RIIb1 activates
phosphatase SHIP1. SHIP1
converts PI(3,4,5)P3 into
PI(3,4)P2, which is the second messenger that activates
PDK and AKT .
BTK is required for B cell development and BCR function.
Cross-linking of BCR induces phosphorylation of BTK by
Lyn . BTK
activates both phospholipase isoforms PLC-gamma-1 and
PLC-gamma-2 , .
Phospholipase PLC-beta is activated by G-proteins, such
as G beta/gamma. Phospholipases
PLC-beta and -gamma catalyze
the hydrolysis of PI(4,5)P2 to form
IP3 and DAG.
IP3, being released into the cytoplasm, binds to
IP3R (IP3 Receptor) on the surface of Endoplasmic Reticulum
and mobilizes Ca(II) from internal stores .
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