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Non-receptor tyrosine kinase based receptor

Tyrosine kinase Ligand receptor

FIGURE 7-2 Major categories of signaling receptors in the immune system. Depicted here are a receptor that uses a non-receptor tyrosine kinase, a receptor tyrosine kinase, a nuclear receptor that binds its ligand and can then influence transcription, a seven-transmembrane receptor linked to heterotrimeric G proteins, and Notch, which recognizes a ligand on a distinct cell and is cleaved, yielding an intracellular fragment (IC Notch) that can enter the nucleus and influence transcription of specific target genes.

FIGURE 7-2 Major categories of signaling receptors in the immune system. Depicted here are a receptor that uses a non-receptor tyrosine kinase, a receptor tyrosine kinase, a nuclear receptor that binds its ligand and can then influence transcription, a seven-transmembrane receptor linked to heterotrimeric G proteins, and Notch, which recognizes a ligand on a distinct cell and is cleaved, yielding an intracellular fragment (IC Notch) that can enter the nucleus and influence transcription of specific target genes.

Cellular receptors are grouped into several categories based on the signaling mechanisms they use and the intracellular biochemical pathways they activate (Fig. 7-2):

• Receptors that use non-receptor tyrosine kinases.

In this category of membrane receptors the ligand-binding chains have no intrinsic catalytic activity, but a separate intracellular tyrosine kinase, known as a non-receptor tyrosine kinase, participates in receptor activation by phosphorylating specific motifs on the receptor or on other proteins associated with the receptor (see Fig. 7-1). A family of receptors called immune receptors, some of which recognize antigens while others recognize the Fc portions of antibodies, all use non-receptor tyrosine kinases to initiate signaling. Apart from the immune receptor family, some cytokine receptors, discussed later in this chapter, also use non-receptor tyrosine kinases. Integrins, key adhesion receptors in the immune system, also signal by activating non-receptor tyrosine kinases.

• Receptor tyrosine kinases (RTKs) are integral membrane proteins that activate an intrinsic tyrosine kinase domain (or domains) located in their cytoplas-mic tails when they are cross-linked by multivalent extracellular ligands (see Fig. 7-2). An example of an RTK relevant to blood cell formation is the c-Kit protein. This RTK has extracellular Ig domains that bind to a ligand known as stem cell factor. Interaction with stem cell factor leads to dimerization of c-Kit and activation of the cytosolic kinase domains of the dimer-ized receptor. Signaling through c-Kit contributes to the initiation of hematopoiesis and lymphopoiesis. Other examples of RTKs include the insulin receptor, the epidermal growth factor receptor, and the platelet-derived growth factor receptor.

• Nuclear receptors. The binding of a lipid-soluble ligand to its nuclear receptor (see Fig. 7-2) results in the ability of the latter either to induce transcription or to repress gene expression. Nuclear hormone receptors, such as the vitamin D receptor and the glucocorticoid receptor, can influence events that range from the development of the immune system to the modulation of cytokine gene expression.

• Seven-transmembrane receptors are polypeptides that traverse the plasma membrane seven times, because of which they are sometimes called serpentine receptors (see Fig. 7-2). Because these receptors function by activating associated GTP-binding proteins (G proteins), they are also commonly called G protein-coupled receptors (GPCRs). A

conformational change induced by the binding of ligand to this type of receptor permits the activation of an associated heterotrimeric G protein, which initiates downstream signaling events. Examples of this category of receptors that are relevant to immunity and inflammation include receptors for leukotrienes, prostaglandins, histamine, complement fragments C3a and C5a, bacterial f-met-leu-phe peptide, and all che-mokines (see Chapter 3). Different types of G proteins linked to distinct GPCRs may activate or inhibit different downstream effectors. The two major enzymes that GPCRs activate are adenylate cyclase, which converts ATP to the effector molecule cAMP, capable of activating numerous cellular responses, and phospho-lipase C, which also triggers multiple signals as discussed later.

• Other classes of receptors. Other categories of receptors have long been known to be important in embryonic development and in certain mature tissues, and their functions in the immune system have more recently begun to emerge. Receptor proteins of the Notch family (see Fig. 7-2) are involved in development in a wide range of species. The association of specific ligands with receptors of this family leads to proteolytic cleavage of the receptor and the nuclear translocation of the cleaved cytoplasmic domain (intracellular Notch), which functions as a component of a transcription complex. Notch proteins contribute to cell fate determination during lymphocyte development (see Chapter 8) and may also influence the activation of mature lymphocytes. A group of ligands called Wnt proteins can influence lymphopoiesis. Signaling through transmembrane receptors for these proteins can regulate the levels of P-catenin, which facilitates the transcriptional activity of proteins that contribute to B and T cell development, as discussed in Chapter 8. Numerous other signaling receptors and pathways first discovered in non-immune cell populations are now beginning to be analyzed in the context of lymphocyte biology. We will not attempt to comprehensively consider all these pathways in this chapter.

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