initiates an additional signaling pathway leading from the B-cell receptor (see Fig. 7.27). Thus, the B-cell co-receptor serves to strengthen the signal resulting from antigen recognition. The role of the third component of the B-cell receptor complex, CD81 (TAPA-1), is as yet unknown.
Once activated, Syk phosphorylates the scaffold protein SLP-65 (also known as BLNK). Like LAT and SLP-76 in T cells, SLP-65 functions as a composite of these two proteins, providing multiple sites for tyrosine phosphorylation and recruiting a variety of SH2-containing proteins, including enzymes and adaptor proteins, to form several distinct multiprotein signaling complexes that can act in concert. As in T cells, a key signaling protein is the phospholipase PLC-γ, which is activated with the aid of the B cell-specific Tec kinase Bruton’s tyrosine kinase (Btk) and hydrolyzes PIP2 to form DAG and IP3 (see Fig. 7.27). As discussed for the T-cell receptor, signaling by calcium and DAG leads to the activation of downstream transcription factors. A deficiency in Btk (which is encoded by a gene on the X chromosome) prevents the development and functioning of B cells, resulting in the disease X-linked agammaglobulinemia, which is characterized by a lack of antibodies. Besides Btk, mutations in other signaling molecules in B cells, including receptor chains and SLP-65, have been linked to B-cell immunodeficiencies (see Chapter 8).
Several other downstream pathways described for TCR signaling are also shared with BCR signaling, and are dependent on the adaptor protein SLP-65. These include the Vav-dependent induction of actin polymerization by Cdc42 and WASp, and the recruitment and activation of small GTPases that promote integrin adhesion (see Fig. 7.27). In the case of B-cell recognition of
B-cell receptor (BcR) signaling is greatly enhanced when the antigen is tagged by complement fragments, engaging the B-cell co-receptor together with the B-cell antigen receptor. cleavage of the antigen-bound complement component c3 to c3dg (see fig. 2.30) allows the tagged antigen to bind to the cell-surface protein cd21 (complement receptor 2, cR2), a component of the B-cell co-receptor complex, which also includes cd19 and cd81 (Tapa-1). cross-linking and clustering of the co-receptor with the antigen receptor result in the phosphorylation of tyrosine residues in the iTam sequences of the cytoplasmic domains of the BcR signaling subunits, igα and igβ. The Src-family kinase also phosphorylates tyrosine residues in the cytoplasmic domain of cd19. The phosphorylated iTams in igα and igβ recruit and activate the tyrosine kinase Syk, which functions similarly to Zap-70 in T cells. The phosphorylated tail of cd19 recruits pi 3-kinase, leading to pip3 generation in the plasma membrane. activated Syk phosphorylates the membrane-associated scaffold protein SLp-65, which associates with the plasma membrane by binding cin85. pip3 recruits pdK1 and akt, leading to akt activation. phosphorylated SLp-65 and pip3 recruit the Tec-family tyrosine kinase Btk and pLc-γ, leading to Btk phosphorylation and activation of pLc-γ. phosphorylated SLp-65 and pip3 also recruit vav, nck, and inactive WaSp. vav activates small GTpases that activate WaSp, leading to actin polymerization; the activated GTpases also induce integrin aggregation and conversion of Lfa-1 to the high-affinity binding state.