Y-27632 Seliciclib Pacritinib

assays and disease models. Pacritinib B cell activa-
tion is dependent on two distinct signals??the initial is antigen
binding to the B cell receptor (BCR), followed by presenta-
tion from the antigen over the B cell surface.

The 2nd activa-
tion signal is carried out as a result of cell-to-cell interaction
amongst B cells and T cells.

Exclusively, CD40 ligand
expressed to the surface of activated T cells associates with
the CD40 receptor (CD40R) expressed on the surface of B
Figure 1. Signaling pathways elicited
on B cell activation. Binding www.selleckchem.com/products/Y-27632.html of antigen
to the B cell receptor (BCR) outcomes
in receptor aggregation and the
activation of the series of tyrosine kinases
that incorporates lyn, spleen tyrosine
kinase (syk), and Bruton??s tyrosine
kinase (BTK). Collectively, they kind
a signaling complex that activates
multiple downstream effectors.

The
subsequent activation of phospholipase
C-?? (PLC??) catalyzes the breakdown of
phosphatidylinositol 4,5 bisphosphate
(PIP2
) to inositol triphosphate (IP3
)
and diacylglycerol (DAG).

IP3
mediates
release of Ca
2+
from intracellular stores
which is measured in the FLIPR-based
technology. In parallel, DAG and Ca
2+

activate CALDAG-GEF (Ca
2+
and DAG
guanine nucleotide exchange aspect)
and Rap1, which eventually converts
LFA-1 to a high-affinity conformation
capable of associating with intercellular
adhesion molecule 1 (ICAM-1)
expressed on the target cell.


7?C10cells. On activation, B cells proliferate, differentiate, and
regulate antibody secretion.
3,4
These processes are tightly
regulated.

Importantly, dysregulation of B cell activity con-
tributes to the disorder pathology related with autoimmune
conditions, for instance systemic lupus and rheumatoid arthritis.


5,6
The signaling cascades elicited on B cell activation are
illustrated in Figure 1.

Briefly, engagement of BCR and/or
CD40R elicits a series of signaling cascades that coalesce at
the level of Bruton??s tyrosine kinase (BTK). BTK is phos-
phorylated by kinases, which include spleen tyrosine kinase (SYK)
and phosphatidylinositol-3 kinase (PI3K).
7,8
Once acti-
vated, BTK phosphorylates and activates phospholipase
C-?? (PLC??) that offers rise to the breakdown of phosphati-
dylinositol 4,5 bisphosphate (PIP2
) for the second messen-
ger??s inositol http://www.selleckchem.com/products/Roscovitine.html triphosphate (IP3
) and diacylglycerol (DAG).


IP3
diffuses towards the endoplasmic reticulum and binds to IP3
-
gated calcium channels releasing Ca
2+
into the cytoplasm.


Within this scenario, the FLIPR platform measures the release of
calcium following BCR-dependent activation.

The two DAG
and Ca
2+
activate the calcium and diacylglycerol binding
guanine nucleotide exchange aspect (CALCADG-GEF1). CALDAG-GEF1 is often a Rap1-specific guanine nucleotide
exchange element that activates Rap1.
9
Rap1 translocates to
the membrane of B cells and, in concert with adapter pro-
teins for example RIAM and Talins, converts low-affinity lym-
phocyte function-associated antigen 1 (LFA-1) to a
higher-af