B cell activation through BCR

The BCR is a complex with a hetero-oligomeric structure in which antigen recognition and signal transduction are compartmentalized into distinct subunits. The antigen recognition subunit of the BCR is a clonally-distributed membrane-bound Ig, a tetrameric complex of heavy and light chains, whereas the signal transduction subunit is a disulfide-linked heterodimer composed of Iga (CD79a), a mb-1 gene product, and Ig/3 (CD79b), a B29 gene product (Figure 1). Both Iga and Ig/3 chains contain within their cytoplasmic domains a sequence motif (immunoreceptor tyrosine-based activation motif, ITAM), D/E-X7-D/E-X2-Y-X2-L/I-X7-Y-X2-L/I, which is also found in the cytoplasmic tails of the signal transducers of the TCR and of Fc receptors (Figure 2).

Stimulation of B cells through the BCR results in rapid increases in tyrosine phosphorylation on a number of proteins and induces an increase of phos-phatidylinositol and mobilization of cytoplasmic free calcium. Though none of the BCR subunits contains intrinsic protein tyrosine kinase (PTK) activity, the BCR associates with two types of cytoplasmic PTKs: Src family PTKs, including Lyn, Fyn, Blk and Lck, and the more distantly related PTK, Syk (Figure 1). Activation of these PTKs through ligation of the BCR by antigen leads to the phosphorylation of the two tyrosine residues within the ITAM in Iga and Ig/3, which in turn leads to recruitment and activation of additional PTKs. The activated PTKs including Btk appear to phosphorylate numerous cellular proteins involved in intracellular signaling pathways, such as the adaptor protein She in the Ras pathway, phospholipase C (PLC)--y2, GTPase-activating protein (GAP), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and Vav as well as HS-1 (Figure 1). The tyrosine phosphorylation of PLC-y2 increases its activity to convert phosphatidylinositol 4,5-bisphosphate into the two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates protein kinase C while IP3 causes Ca2+ release from intracellular stores (Figure 1).

The regulated signal transduction through the BCR can be achieved by coordinated actions of PTKs and protein tyrosine phosphatases (PTPs). CD45 is a transmembrane PTP expressed on hematopoietic

C045 BCH

C045 BCH

cells and plays a critical role in B cell activation following ligation of the BCR (Figure 1). The regulation of Src family PTKs by CD45 appears to be one of the bases for requirement of CD45 in antigen-induced BCR signaling. Since Src family PTKs contain a negative regulatory tyrosine phosphorylation site at their carboxyl termini, dephosphorylation of this site by CD45 results in an increase of their kinase activity. The phosphorylated tyrosine residues within ITAM of Iga and Ig/3 also appear to be substrates for CD45. The importance of CD45 in BCR signaling has been confirmed by generating CD45-deficient mice in which B cells are completely refractory to proliferation stimulated by anti-IgM antibody.

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