General principles of signal transduction and propagation.
In this part of the chapter we review briefly some general principles of receptor action and signal transduction that are common to many of the pathways discussed here. All cell-surface receptors that have a signaling function either are transmembrane proteins themselves or form parts of protein complexes that link the exterior and interior of the cell. Different classes of receptors trans-duce extracellular signals in a variety of ways. A common theme among the receptors covered in this chapter is that ligand binding results in the activation of an intracellular enzymatic activity.
General principles of signal transduction and propagation.
antigen receptor signaling and lymphocyte activation.
co-stimulatory and inhibitory receptors modulate antigen receptor signaling in T and B lymphocytes.
7-1 Transmembrane receptors convert extracellular signals into intracellular biochemical events.
The enzymes most commonly associated with receptor activation are the protein kinases. This large group of enzymes catalyzes the covalent attachment of a phosphate group to a protein, a reversible process called phosphorylation. For receptors that use protein kinases, the binding of ligand to the extracellular part of the receptor allows the receptor-associated protein kinase to become ‘active’—that is, to phosphorylate its intracellular substrate—and thus to propagate the signal. As we shall see, receptor-associated kinases can become activated in various ways, such as by undergoing modifications to the kinase itself that alter its intrinsic catalytic efficiency or by changes in subcellular localization that increase access to its biochemical substrates.
In animals, protein kinases phosphorylate proteins on three amino acids— tyrosine, serine, or threonine. Most of the enzyme-linked receptors we discuss in detail in this chapter activate tyrosine protein kinases. Tyrosine kinases are specific for tyrosine residues, whereas serine/threonine kinases phosphorylate serine and threonine residues; less common are dual-specificity kinases that phosphorylate both tyrosine and serine/threonine residues in their substrates. Protein tyrosine phosphorylation is much less common than serine/threonine phosphorylation in general, and is employed mainly in signaling pathways. One large group of receptors—the so-called receptor tyrosine kinases— carry a kinase activity within the cytoplasmic region of the receptor itself (Fig. 7.1, top panel). This group contains receptors for many growth factors; lymphocyte receptors of this type include Kit and FLT3, which are expressed on developing lymphocytes in addition to other hematopoietic progenitor cells and are discussed in Chapter 8. The receptor for transforming growth factor-β (TGF-β), an important regulatory cytokine produced by many cells, is a receptor serine/threonine kinase.
Even more important to the function of mature lymphocytes are receptors that have no intrinsic enzymatic activity themselves but associate with intracellular tyrosine kinases. The antigen receptors on B lymphocytes and T lymphocytes are of this type, as are the receptors for some types of cytokines. Ligand binding to the extracellular domain of such receptors causes particular amino acid residues in their cytoplasmic domains to become phosphorylated by specific cytoplasmic tyrosine kinases (see Fig. 7.1, bottom panel). These nonreceptor kinases either can be constitutively associated with the cytoplasmic domains of the receptors, as with many cytokine receptors, or may become associated with the receptors when they bind their ligands, as is the case for the antigen receptors.