Stimulation through antigen receptors can be modified significantly by signals through coreceptors. Recall that co-stimulation through CD28 is an essential feature of effective positive stimulation of T lymphocytes, while signaling through CTLA-4 inhibits the response of the T cell. In B cells
Small G-protein pathways
Small G-protein pathways
Ca2+-mediated pathways r
Changes in pattern of gene expression
> Functional changes in cells Differentiation
Some of the many signal-transduction pathways activated by the BCR. In one pathway, Syk activates PLC72 by tyrosine phosphorylation. PLC72 then hydrolyzes PIP2, a membrane phospholipid, to produce the second messengers DAG and IP3. DAG and Ca2+ released by the action of IP3 collaboratively activate the PKC, which induces additional signal-transduction pathways. The activated receptor complex also generates signals that activate the Ras pathway. Activated Ras initiates a cascade of phosphorylations that culminates in the activation of transcription factors that up-regulate the expression of many genes.
The B-cell coreceptor is a complex of three proteins: CD19, CR2 (CD21), and TAPA-1 (CD81) (Figure 11-9). CD 19, a member of the immunoglobulin superfamily, has a long cyto-plasmic tail and three extracellular domains. The CR2 component is a receptor of C3d, a breakdown product of the complement system, which is an important effector mechanism for destroying invaders (Chapter 13); note that the involvement of C3d in the pathway for coreceptor activity reveals different arms of the immune system interacting with each other. CR2 also functions as a receptor for a membrane molecule and the transmembrane protein TAPA-1. In addition to the stimulatory coreceptor, another molecule, CD22, which is constitutively associated with the B-cell receptor in resting B cells, delivers a negative signal that makes B-cells more difficult to activate. As shown in Figure 11-9, the CR2 component of the coreceptor complex binds to complement-coated antigen that has been captured by the mIg on the B cell. This crosslinks the coreceptor to the BCR and allows the CD19 component of the coreceptor to interact with the Ig-a/Ig- p component of the BCR. CD19 contains six tyrosine residues in its long cytoplas-mic tail and is a major substrate of the protein tyrosine kinase activity that is mediated by crosslinkage of the BCR. Phospho-rylation of CD19 permits it to bind a number of signaling molecules, including the protein tyrosine kinase Lyn.
The delivery of these signaling molecules to the BCR complex contributes to the activation process, and the coreceptor
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