B-cell Receptor - Signaling Pathways of The B-Cell Receptor

Signaling Pathways of The B-Cell Receptor

There are several signaling pathways that the B-Cell Receptor can follow through. Of those known, there can be intracellular signaling through the PLCy/calcium/NFAT pathway, the PI3K pathway, the IKK/NF-κB pathway, and canonical ERK pathway.

1. IKK/NF-κB Transcription Factor Pathway: CD79 and other proteins, microsignalosomes, go to activate PLCɣ 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.