s, including
Blk,
LYN, and
FYN and the
SYK and
BTK tyrosine kinases. As such, the process catalyzes the formation of a ‘signalosome’ that consists of the aforementioned tyrosine kinases, the BCR and the
adaptor proteins, for instance,
BLNK and
CD19, as well as signaling molecules, such as
PI3K,
PLCy2, and
VAV. There are several signaling pathways that the B-cell receptor can follow through. The physiology of B cells is intimately connected with the function of their B-cell receptor. The BCR signaling pathway is initiated when the mIg subunits of the BCR bind a specific antigen. The initial triggering of the BCR is similar for all receptors of the
non-catalytic tyrosine-phosphorylated receptor family. The binding event allows phosphorylation of
immunoreceptor tyrosine-based activation motifs (ITAMs) in the associated Igα/Igβ heterodimer subunits by the tyrosine kinases of the
Src family, including
Blk,
Lyn, and
Fyn. Multiple models have been proposed how BCR-antigen binding induces phosphorylation, including conformational change of the receptor and aggregation of multiple receptors upon antigen binding. Tyrosine kinase
Syk binds to and is activated by phosphorylated ITAMs and in turn phosphorylates scaffold protein
BLNK on multiple sites. After phosphorylation, downstream signalling molecules are recruited to BLNK, which results in their activation and the transduction of the signal to the interior. •
IKK/NF-κB Transcription Factor Pathway: CD79 and other proteins, microsignalosomes, go to activate
PLC-γ after antigen recognition by the BCR and before it goes to associate into the
c-SMAC. It then cleaves
PIP2 into
IP3 and DAG (
diacylglycerol). IP3 acts as a
second messenger to dramatically increase ionic calcium inside the
cytosol (via release from the
endoplasmic reticulum or influx from the extracellular environment via
ion channels). This leads to eventual activation of
PKCβ from the calcium and DAG. PKCβ phosphorylates (either directly or indirectly) the
NF-κB signaling complex protein
CARMA1 (the complex itself comprising CARMA1,
BCL10, and
MALT1). These result in recruitment and summoning of the IKK (
IkB kinase),
TAK1, by several ubiquitylation enzymes also associated with the CARMA1/BCL10/MALT1 complex. MALT1 itself is a
caspase-like protein that cleaves A20, an inhibitory protein of NF-κB signaling (which acts by deubiquitylating NF-κB's ubiquitylation substrates, having an inhibitory effect). TAK1 phosphorylates the IKK trimer after it too has been recruited to the signaling complex by its associated ubiquitylation enzymes. IKK then phosphorylates
IkB (an inhibitor of and bound to NF-κB), which induces its destruction by marking it for proteolytic degradation, freeing cytosolic NF-κB. NF-κB then migrates to the nucleus to bind to DNA at specific response elements, causing recruitment of transcription molecules and beginning the transcription process. • Ligand binding to the BCR also leads to the phosphorylation of the protein BCAP. This leads to the binding and activation of several proteins with phosphotyrosine-binding SH2 domains. One of these proteins is PI3K. Activation of PI3K leads to PIP2 phosphorylation, forming PIP3. Proteins with PH (Pleckstrin homology) domains can bind to the newly created PIP3 and become activated. These include proteins of the FoxO family, which stimulate cell cycle progression, and protein kinase D, which enhances glucose metabolism. Another important protein with a PH domain is Bam32. This recruits and activates small GTPases such as Rac1 and Cdc42. These, in turn, are responsible for the cytoskeletal changes associated with BCR activation by modifying actin polymerisation. ==Contributions of mechanical forces to activation==