617 β2-AR Gγ G 15 Gα β Cell Signaling and Signal Transduction: Communication Between Cells 15.1 The Basic Elements of Cell Signaling Systems The English poet John Donne expressed his belief in the 15.2 A Survey of Extracellular Messengers and Their interdependence of humans in the phrase “No man is an island.” Receptors The same can be said of the cells that make up a complex multi- cellular organism. Most cells in a plant or animal are specialized 15.3 G Protein-Coupled Receptors and Their Second to carry out one or more specific functions. Many biological Messengers processes require various cells to work together and to 15.4 Protein-Tyrosine Phosphorylation as a Mechanism coordinate their activities. To make this possible, cells have to for Signal Transduction communicate with each other, which is accomplished by a 15.5 The Role of Calcium as an Intracellular Messenger process called cell signaling . Cell signaling makes it possible 15.6 Convergence, Divergence, and Cross-Talk for cells to respond in an appropriate manner to a specific environmental stimulus. Among Different Signaling Pathways Cell signaling affects virtually every aspect of cell structure 15.7 The Role of NO as an Intercellular Messenger and function, which is one of the primary reasons that this 15.8 Apoptosis (Programmed Cell Death) chapter appears near the end of the book. On one hand, an THE HUMAN PER SP ECTIVE: Disorders Associated understanding of cell signaling requires knowledge about other with G Protein-Coupled Receptors types of cellular activity. On the other hand, insights into cell signaling can tie together a variety of seemingly independent THE HUMAN PER SP ECTIVE: Signaling Pathways and cellular processes. Cell signaling is also intimately involved in the Human Longevity Three-dimensional, X-ray crystallographic structure of a signaling complex between a ␤2-adrenergic receptor ( ␤2-AR), which is a represen- tative member of the G protein-coupled receptor (GPCR) superfamily, and a heterotrimeric G protein. The ␤2-AR is shown in green and the three subunits of the G protein are shown in orange, cyan, and purple. The plasma membrane is shown as a grey shadow. GPCRs are integral membrane proteins characterized by their seven transmembrane helices. As a group, these proteins bind an astonishing array of biological messengers, which constitutes the first step in eliciting many of the body’s most basic responses. [CONTINUED ON NEXT PAGE ] 618 Binding of an agonist (e.g., epinephrine) to the binding pocket in the extracellular domain of the ␤2 AR causes a conformational change in the receptor that causes it to bind the G protein, which transmits the signal into the cell, inducing responses such as increased heart rate and relaxation of smooth muscle cells. Beta-adrenergic receptors are the targets of a number of important drugs, including ␤-blockers, which are widely prescribed for the treatment of high blood pressure and heart arrhythmias. GPCRs had been very difficult to crystallize so that high-resolution structures of these important proteins had been lacking. This situation is now changing as the result of recent advances in crystallization technology. In this case, crystallization of the signaling complex was accomplished using two additional small proteins (not shown in the image) that bound to the ␤2 AR and the G protein to stabilize the complex during the crystallization process. (C OURTESY OF SØREN G. F. R ASMUSSEN , A NDREW C. K RUSE , AND BRIAN K. K OBILKA .) regulation of cell growth and division. This makes the study of lose the ability to control cell division and develop into a cell signaling crucially important for understanding how a cell can malignant tumor. 15.1 | The Basic Elements steroids and neurotransmitters ) to small, soluble protein hor- mones (e.g., glucagon and insulin) to huge glycoproteins bound of Cell Signaling Systems to the surfaces of other cells. Cells can only respond to a partic- It may be helpful to begin the discussion of this complex subject ular extracellular message if they express receptors that specifi- by describing a few of the general features that are shared by cally recognize and bind that messenger molecule (step 2). The most signaling pathways. Cells usually communicate with each molecule that binds to the receptor is called a ligand . Different other through extracellular messenger molecules . Extracellu- types of cells possess different complements of receptors, which lar messengers can travel a short distance and stimulate cells allow them to respond to different extracellular messengers. that are in close proximity to the origin of the message, or they Even cells that share a specific receptor may respond very dif- can travel throughout the body, potentially stimulating cells ferently to the same extracellular messenger. Liver cells and that are far away from the source. In the case of autocrine signal- smooth muscle cells both possess the ␤2-adrenergic receptor ing, the cell that is producing the messenger expresses receptors shown in the chapter-opening image on page 617. Activation of on its surface that can respond to that messenger (Figure this receptor by circulating adrenaline leads to glycogen break- 15.1 a). Consequently, cells releasing the message will stimulate down in a liver cell and relaxation in a smooth muscle cell. (or inhibit) themselves. During paracrine signaling (Figure These different outcomes following interaction with the same 15.1 b), messenger molecules travel only short distances through initial stimulus can be traced to different intracellular proteins the extracellular space to cells that are in close proximity to the that become engaged in the response in these two types of cells. cell that is generating the message. Paracrine messenger mole- Thus the type of activities in which a cell engages depends both cules are usually limited in their ability to travel around the on the stimuli that it receives and the intracellular machinery on on Between Cells body because they are inherently unstable, or they are degraded that it possesses at that particular time in its life. by enzymes, or they bind to the extracellular matrix. Finally, In most cases, the extracellular messenger molecule binds during endocrine signaling, messenger molecules reach their tar- to a receptor at the outer surface of the responding cell. This get cells via passage through the bloodstream (Figure 15.1 c). interaction induces a conformational change in the receptor Endocrine messengers are also called hormones , and they typi- that causes the signal to be relayed across the membrane to the cally act on target cells located at distant sites in the body. receptor’s cytoplasmic domain (step 3, Figure 15.2). Once it An overview of cellular signaling pathways is depicted in has reached the inner surface of the plasma membrane, there Figure 15.2. Cell signaling is initiated with the release of a mes- are two major routes by which the signal is transmitted into senger molecule by a cell that is engaged in sending messages to the cell interior, where it elicits the appropriate response. The other cells in the body (step 1, Figure 15.2). The particular route taken depends on the type of receptor that is extracellular environments of cells contain hundreds of different activated. In the following discussion, we will focus on these informational molecules, ranging from small compounds (e.g., two major routes of signal transduction, but keep in mind Cell Cell Signaling and Signal Transduction: Communicati (a) (b) (c) Figure 15.1 Autocrine ( a), paracrine ( b), and endocrine ( c) types of intercellular signaling. Chapter Chapter 15 619 there are other ways that extracellular signals can have an im- I Another type of receptor (Section 15.4) transmits a signal pact on a cell. For example, we saw on page 169 how neuro- by transforming its cytoplasmic domain into a recruiting transmitters act by opening plasma membrane ion channels station for cellular signaling proteins (step 4a). Proteins and on page 525 how steroid hormones diffuse through the interact with one another, or with components of a cellular plasma membrane and bind to intracellular receptors. In the membrane, by means of specific types of interaction two major routes discussed in this chapter: domains, such as the SH3 domain discussed on page 62. I One type of receptor (Section 15.3) transmits a signal Whether the signal is transmitted by a second messenger from its cytoplasmic domain to a nearby enzyme (step 4), or by protein recruitment, the outcome is similar; a protein that which generates a second messenger (step 5). Because it is positioned at the top of an intracellular signaling pathway is brings about (effects) the cellular response by generating a activated (step 6, Figure 15.2). Signaling pathways are the in- second messenger, the enzyme responsible is referred to as formation superhighways of the cell. Each signaling pathway an effector . Second messengers are small substances that consists of a series of distinct proteins that operate in sequence typically activate (or inactivate) specific proteins. Depend- (step 7). Most “signaling proteins” are constructed of multiple ing on its chemical structure, a second messenger may dif- domains, which allows them to interact in a dynamic way with fuse through the cytosol or remain embedded in the lipid a number of different partners, either simultaneously or se- bilayer of a membrane. quentially. This type of modular construction is illustrated by the Grb2 and IRS-1 proteins depicted in Figures 15.20 and 15.25 a, respectively. Unlike Grb2 and IRS-1, which function Signaling cell exclusively in mediating protein-protein interactions, many signaling proteins also contain catalytic and/or regulatory do- 1 mains that give them a more active role in a signaling pathway. Extracellular signaling molecule (first messenger) Each protein in a signaling pathway typically acts by altering the conformation of the subsequent (or downstream) protein in the series, an event that activates or inhibits that pro- Transmembrane tein (Figure 15.3).