In many cases, intracellular signaling involves the activation of enzymes that produce small-molecule biochemical mediators known as second messengers (Fig. 7.7). These mediators can diffuse throughout the cell, enabling the signal to activate a variety of target proteins. The enzymatic production of second messengers also serves the dual purpose of achieving concentrations of them sufficient to activate the next stage of the pathway and of amplifying the signaling cascade. The second messengers generated by receptors that signal via tyrosine kinases include calcium ions (Ca2+) and a variety of membrane lipids and their soluble derivatives. Although some of these lipid messengers are confined to membranes, they can move within them. A second messenger binding to its target protein typically induces a conformational change that allows the protein to be activated.
Summary.
Cell-surface receptors serve as the front line of a cell’s interaction with its environment; they sense extracellular events and convert them into biochemical signals for the cell. As most receptors sit in the plasma membrane, a critical step in the transduction of extracellular signals to the interior of the cell is recruitment of intracellular proteins to the membrane and changes in the composition of the membrane surrounding the receptor. Many immune receptors operate by activating tyrosine kinases to transmit their signals onward, often using scaffolds and adaptors to form large multiprotein signaling complexes. Both the qualitative and quantitative changes that take place in the composition of these signaling complexes determine the character of the response and biological outcomes. Formation of signaling complexes is mediated by a wide variety of protein-interaction domains, or modules, including the SH2, SH3, and PH domains found in proteins. In many cases, the increase in enzymatically produced small-molecule signaling intermediates called second messengers regulates and amplifies the signaling cascade. Termination of signaling involves protein dephosphorylation as well as ubiquitin-mediated protein degradation.
Antigen receptor signaling and lymphocyte activation.
Fig. 7.7 Signaling pathways amplify the initial signal. amplification of the initial signal is an important element of most signal transduction pathways. one means of amplification is a kinase cascade (left panel), in which protein kinases successively phosphorylate and activate each other. in this example, taken from a commonly used kinase cascade (see fig. 7.19), activation of the kinase Raf results in the phosphorylation and activation of a second kinase, mek, that phosphorylates yet another kinase, erk. as each kinase can phosphorylate many different substrate molecules, the signal is amplified at each step, resulting in a huge amplification of the initial signal. another method of signal amplification is the generation of second messengers (center and right panels). in this example, signaling results in the release of the second messenger calcium (ca2+) from intracellular stores into the cytosol or its influx from the extracellular environment. ca2+ release from the endoplasmic reticulum (eR) is shown here. The sharp increase in free ca2+ in the cytoplasm can potentially activate many downstream signaling molecules, such as the calcium-binding protein calmodulin. calcium binding induces a conformational change in calmodulin, which allows it to bind to and regulate a variety of effector proteins.
The ability of T cells and B cells to recognize and respond to their specific antigen is central to adaptive immunity. As described in Chapters 4 and 5, the B-cell antigen receptor (BCR) and the T-cell antigen receptor (TCR) are made up of antigen-binding chains—the heavy and light immunoglobulin chains