Signaling at the Cell Surface

13 SIGNALING AT THE CELL SURFACE Three-dimensional structure of the G protein ␤ (blue) and ␥ (purple) complex as obtained by x-ray crystallography. o cell lives in isolation. In eukaryotic microorgan- plasma membrane and bind to intracellular receptors. Sig- isms such as yeast, slime molds, and protozoans, se- naling from such intracellular receptors is discussed in Ncreted molecules called pheromones coordinate the Chapter 11. aggregation of free-living cells for sexual mating or differ- In this and the next two chapters, we focus on signaling entiation under certain environmental conditions. Yeast from a diverse group of receptor proteins located in the mating-type factors are a well-understood example of plasma membrane (Figure 13-1). The signaling molecule pheromone-mediated cell-to-cell signaling (Chapter 22). acts as a ligand, which binds to a structurally complemen- More important in plants and animals are extracellular sig- tary site on the extracellular or membrane-spanning do- naling molecules that function within an organism to control mains of the receptor. Binding of a ligand to its receptor metabolic processes within cells, the growth and differentia- causes a conformational change in the cytosolic domain or tion of tissues, the synthesis and secretion of proteins, and domains of the receptor that ultimately induces specific cel- the composition of intracellular and extracellular fluids. Ad- lular responses. The overall process of converting signals jacent cells often communicate by direct cell-cell contact. For into cellular responses, as well as the individual steps in this example, gap junctions in the plasma membranes of adjacent cells permit them to exchange small molecules and to coordinate metabolic responses. Other junctions between adja- OUTLINE cent cells determine the shape and rigidity of many tissues; other interactions adhere cells to the extracellular matrix. 13.1 Signaling Molecules and Cell-Surface Such cell-cell and cell-matrix interactions, which are covered Receptors in Chapter 6, may also initiate intracellular signaling via 13.2 Intracellular Signal Transduction pathways similar to those discussed in this and subsequent chapters. 13.3 G Protein–Coupled Receptors That Activate Extracellular signaling molecules are synthesized and re- or Inhibit Adenylyl Cyclase leased by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. 13.4 G Protein–Coupled Receptors That Regulate In multicellular organisms, an enormous variety of chemi- Ion Channels cals, including small molecules (e.g., amino acid or lipid de- 13.5 G Protein–Coupled Receptors That Activate rivatives, acetylcholine), peptides, and proteins, are used in Phospholipase C this type of cell-to-cell communication. Some signaling molecules, especially hydrophobic molecules such as steroids, 13.6 Activation of Gene Transcription retinoids, and thyroxine, spontaneously diffuse through the by G Protein–Coupled Receptors 533 534 CHAPTER 13 • Signaling at the Cell Surface Exterior P P Cytosol P P Nucleus P P P P P G protein-coupled Cytokine receptors Receptor tyrosine TGFβ receptors Hedgehog (Hh) Wnt receptors Notch receptor receptors kinases receptors Linked to a trimeric G Associated with Cytosolic domain Cytosolic domain Hh ligand tethered to Palmitoylated Wnt Ligand, Delta, is a protein that controls cytosolic JAK kinases with tyrosine kinase with serine/threonine membrane of ligand binds seven transmembrane the activity of an activity kinase activity signaling cell by transmembrane protein on signaling effector protein (here cholesterol anchor protein receptor cell adenylyl cyclase) complex Activate cytosolic or Activate cytosolic Activate cytosolic Activate Smad Control processing Release an activated Cytosolic domain of nuclear transcription STAT transcription kinases (here MAP transcription factors of transcription factor transcription factor Notch released by factors via several factors by kinase) that trans- in the cytosol by by proteolysis; from a multiprotein proteolysis acts in pathways (here one phosphorylation locate to the nucleus phosphorylation Hh binding causes complex in the association with involving protein and activate nuclear release from cytosol nuclear transcription kinase A) transcription factors cytosolic complex factors by phosphorylation ▲ FIGURE 13-1 Overview of seven major classes of cell- stimulation may lead to activation of cytosolic protein kinases surface receptors discussed in this book. In many signaling that then translocate into the nucleus and regulate the activity of pathways, ligand binding to a receptor leads to activation of nuclear transcription factors. Some activated receptors, transcription factors in the cytosol, permitting them to translocate particularly certain G protein–coupled receptors, also can induce into the nucleus and stimulate (or occasionally repress) changes in the activity of preexisting proteins. [After A. H. Brivanlou transcription of their target genes. Alternatively, receptor and J. Darnell, 2002, Science 295:813.] process, is termed signal transduction. As we will see, signal- transduction pathways may involve relatively few or many 13.1 Signaling Molecules components. and Cell-Surface Receptors We begin this chapter with two sections that describe general principles and techniques that are relevant to most Communication by extracellular signals usually involves the signaling systems. In the remainder of the chapter, we con- following steps: (1) synthesis and (2) release of the signaling centrate on the huge class of cell-surface receptors that ac- molecule by the signaling cell; (3) transport of the signal to tivate trimeric G proteins. Receptors of this type, the target cell; (4) binding of the signal by a specific recep- commonly called G protein–coupled receptors (GPCRs), tor protein leading to its activation; (5) initiation of one or are found in all eukaryotic cells from yeast to man. The more intracellular signal-transduction pathways by the acti- human genome, for instance, encodes several thousand vated receptor; (6) specific changes in cellular function, G protein–coupled receptors. These include receptors in the metabolism, or development; and (7) removal of the signal, visual, olfactory (smell), and gustatory (taste) systems, which often terminates the cellular response (see Figure many neurotransmitter receptors, and most of the receptors 13-1). The vast majority of receptors are activated by bind- for hormones that control carbohydrate, amino acid, and ing of secreted or membrane-bound molecules (e.g., hor- fat metabolism. mones, growth factors, neurotransmitters, and pheromones). 13.1 • Signaling Molecules and Cell-Surface Receptors 535 Some receptors, however, are activated by changes in the signal an adjacent cell by direct contact. Cleavage by an ex- concentration of a metabolite (e.g., oxygen or nutrients) or tracellular protease releases a soluble form of EGF, which by physical stimuli (e.g., light, touch, heat). In E. coli, for can signal in either an autocrine or a paracrine manner. instance, receptors in the cell-surface membrane trigger signaling pathways that help the cell respond to changes Receptors Activate a Limited Number in the external level of phosphate and other nutrients (see Figure 4-18). of Signaling Pathways The number of receptors and signaling pathways that we dis- Signaling Molecules in Animals Operate cuss throughout this book initially may seem overwhelming. Moreover, the terminology for designating pathways can be over Various Distances confusing. Pathways commonly are named based on the In animals, signaling by soluble extracellular molecules can general class of receptor involved (e.g., GPCRs, receptor ty- be classified into three types—endocrine, paracrine, or au- rosine kinases), the type of ligand (e.g., TGF␤, Wnt, Hedge- tocrine—based on the distance over which the signal acts. hog), or a key intracellular signal transduction component In addition, certain membrane-bound proteins act as signals. (e.g., NF-␬B). In some cases, the same pathway may be In endocrine signaling, the signaling molecules, called referred to by different names. Fortunately, as researchers hormones, act on target cells distant from their site of syn- have discovered the molecular details of more and more re- thesis by cells of the various endocrine organs. In animals, an ceptors and pathways, some principles and mechanisms are endocrine hormone usually is carried by the blood or by beginning to emerge. These shared features can help us make other extracellular fluids from its site of release to its target. sense of the wealth of new information concerning cell-to- In paracrine signaling, the signaling molecules released cell signaling. by a cell affect target cells only in close proximity. The con- First, external signals induce two major types of cellular duction by a neurotransmitter of a signal from one nerve cell responses: (1) changes in the activity or function of specific to another or from a nerve cell to a muscle cell (inducing or pre-existing proteins and (2) changes in the amounts of spe- inhibiting muscle contraction) occurs via paracrine signal- cific proteins produced by a cell, most commonly as the result ing (Chapter 7). Many growth factors regulating develop- of modification of transcription factors leading to activation ment in multicellular organisms also act at short range. Some or repression of gene transcription. In general, the first type of of these molecules

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