Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 88

B) exerts a
negative feedback loop that limits platelet activation [ 168 ]. Factor NF

Nuclear factor- κ light chain-enhancer of activated B cells (NF κ

κ B builds a

complex with protein kinase-A that contains inhibitor of NF κ BI κ B α . The latter is

phosphorylated by inhibitor of NF B kinase. This event releases PKA that can then

phosphorylate the actin-dynamics inhibitor vasodilator-stimulated phosphoprotein.
The NF

κ

B-PKA pathway is stimulated by thrombin and collagen. It limits platelet
activation and motility, hence thrombus stability, as it reduces cytoskeletal dynamics
and early-stage aggregation.
Diverse elements of the NF

κ

κ B family in platelets produce different associations

of NF B subunits that initiate different signalings according to the source of platelet

stimulation. Fibrinogen-activated platelets cause platelet spreading via NF

κ

κ Bthat

influences fibrinogen binding to α 2B β 3 -integrin [ 169 ].

Thrombin-activated platelets, but not resting cells, synthesize B-cell lymphoma-3
protein [ 170 ]. Protein BCL3 is a member of the atypical I

B subfamily that acts not
only as a transcriptional coregulator, but also as a component of the autoregulatory
loop via its association with NF

κ

B. In activated platelets, BCL3 interacts with Fyn
kinase to produce a retracted fibrin clot, the clot consisting of aggregated platelets
and a mesh of fibrins.
Furthermore, inhibitor of NF

κ

κ B kinases have other substrates than inhibitors

of NF B, such as AMPK and MAP3K7 kinases [ 171 ]. In platelets, AMPK and

MAP3K7 contribute to signaling for adhesion and aggregation of platelets as well
as exocytosis of mediators.

κ

3.6.6 Other Regulators of the Platelet Function

At least, 3 subtypes of P2 receptors are implicated in platelet activation: P2X 1 ,
P2Y 1 ,andP2Y 12 (Vol. 3 - Chaps. 2. Membrane Ion Carriers and 7. G-Protein-
Coupled Receptors). Ion channel P2X 1 activated by ATP during collagen-induced
platelet activation generates a rapid influx of calcium, which leads to a change
in platelet shape and platelet aggregation. Gq-coupled P2Y 1 receptor also modifies
platelet shape and provokes aggregation via calcium influx. Adenosine diphos-
phate binds to the P2Y 1 receptor. Gi-coupled P2Y 12 receptor that binds ADP
inhibits adenylate cyclase. The activation of phosphatidylinositol 3-kinase by ADP
G-protein-coupled receptors triggers platelet aggregation.
The Wnt-

-catenin signaling pathway functions in human platelets [ 172 ].
Platelets possess Wnt receptors such as Frizzled-4 and -6 receptors as well as LRP5
and LRP6 coreceptors and Disheveled-2 mediator. Wnt3a ligand prevents platelet
activation, dense granule secretion, adhesion, and aggregation [ 172 ]. In addition,
Wnt3a hampers the thrombin-induced activation of RhoA GTPase (non-canonical
Wnt signaling). Among non-genomic functions,

β

β -catenins link adhesion receptors

of the cadherin family to the actin cytoskeleton.