Chapter Introduction

Signal-Transduction Pathways

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Signal-transduction circuits in biological systems have molecular on–off switches that, like those in a computer chip (above), transmit information when “on.” Common among these circuits are those including G proteins (right), which transmit a signal when bound to GTP and are silent when bound to GDP.
[(Left) Astrid & Hanns-Frieder Michler/Science Source.]

OUTLINE

  1. Heterotrimeric G Proteins Transmit Signals and Reset Themselves

  2. Insulin Signaling: Phosphorylation Cascades Are Central to Many Signal-Transduction Processes

  3. EGF Signaling: Signal-Transduction Systems Are Poised to Respond

  4. Many Elements Recur with Variation in Different Signal-Transduction Pathways

  5. Defects in Signal-Transduction Pathways Can Lead to Cancer and Other Diseases

A cell is highly responsive to specific chemicals in its environment: it may adjust its metabolism or alter gene-expression patterns on sensing the presence of these molecules. In multicellular organisms, these chemical signals are crucial to coordinating physiological responses (Figure 14.1). Three examples of molecular signals that stimulate a physiological response are epinephrine (sometimes called adrenaline), insulin, and epidermal growth factor (EGF). When a mammal is threatened, its adrenal glands release the hormone epinephrine, which stimulates the mobilization of energy stores and leads to improved cardiac function. After a full meal, the β cells in the pancreas release insulin, which stimulates a host of physiological responses, including the uptake of glucose from the bloodstream and its storage as glycogen. The release of EGF in response to a wound stimulates specific cells to grow and divide. In all these cases, the cell receives information that a certain molecule within its environment is present above some threshold concentration. The chain of events that converts the message “this molecule is present” into the ultimate physiological response is called signal transduction.

Signal-transduction pathways often comprise many components and branches. They can thus be immensely complicated and confusing. However, the logic of signal transduction can be simplified by examining the common strategies and classes of molecules that recur in these pathways. These principles are introduced here because signal-transduction pathways affect essentially all of the metabolic pathways that we will be exploring throughout the rest of the book.

Figure 14.1: Three signal-transduction pathways. The binding of signaling molecules to their receptors initiates pathways that lead to important physiological responses.

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Signal transduction depends on molecular circuits

Signal-transduction pathways follow a broadly similar course that can be viewed as a molecular circuit (Figure 14.2). All such circuits contain certain key steps:

  1. Release of the Primary Messenger. A stimulus such as a wound or digested meal triggers the release of the signal molecule, also called the primary messenger.

  2. Reception of the Primary Messenger. Most signal molecules do not enter cells. Instead, proteins in the cell membrane act as receptors that bind the signal molecules and transfer the information that the molecule has bound from the external environment to the cell’s interior. Receptors span the cell membrane and thus have both extracellular and intracellular components. A binding site on the extracellular side specifically recognizes the signal molecule (often referred to as the ligand). Such binding sites are analogous to enzyme active sites except that no catalysis takes place within them. The interaction of the ligand and the receptor alters the tertiary or quaternary structure of the receptor so as to induce a structural change on the intracellular side.

  3. Delivery of the Message Inside the Cell by the Second Messenger. Other small molecules, called second messengers, are used to relay information from receptor–ligand complexes. Second messengers are intracellular molecules that change in concentration in response to environmental signals and mediate the next step in the molecular information circuit. Some particularly important second messengers are cyclic AMP (cAMP) and cyclic GMP (cGMP), calcium ion, inositol 1,4,5-trisphosphate (IP3), and diacylglycerol (DAG; Figure 14.3).

    Figure 14.2: Principles of signal transduction. An environmental signal is first received by interaction with a cellular component, most often a cell-surface receptor. The information that the signal has arrived is then converted into other chemical forms, or transduced. Typically, the transduction process comprises many steps. The signal is often amplified before evoking a response. Feedback pathways regulate the entire signaling process.
    Figure 14.3: Common second messengers. Second messengers are intracellular molecules that change in concentration in response to environmental signals. That change in concentration conveys information inside the cell.

    The use of second messengers has several consequences. First, the signal may be amplified significantly: only a small number of receptor molecules may be activated by the direct binding of signal molecules, but each activated receptor molecule can lead to the generation of many second messengers. Thus, a low concentration of signal in the environment, even as little as a single molecule, can yield a large intracellular signal and response. Second, these messengers are often free to diffuse to other cellular compartments where they can influence processes throughout the cell. Third, the use of common second messengers in multiple signaling pathways creates both opportunities and potential problems. Input from several signaling pathways, often called cross talk, may alter the concentration of a common second messenger. Cross talk permits more finely tuned regulation of cell activity than would the action of individual independent pathways. However, inappropriate cross talk can result in the misinterpretation of changes in second-messenger concentration.

  4. Activation of Effectors That Directly Alter the Physiological Response. The ultimate effect of the signal pathway is to activate (or inhibit) the pumps, channels, enzymes, and transcription factors that directly control metabolic pathways, gene expression, and the permeability of membranes to specific ions.

  5. Termination of the Signal. After a cell has completed its response to a signal, the signaling process must be terminated or the cell loses its responsiveness to new signals. Moreover, signaling processes that fail to terminate properly can have highly undesirable consequences. As we will see, many cancers are associated with signal-transduction processes that are not properly terminated, especially processes that control cell growth.

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In this chapter, we will examine components of the three signal-transduction pathways shown in Figure 14.1. In doing so, we will see several classes of adaptor domains present in signal-transduction proteins. These domains usually recognize specific classes of molecules and help transfer information from one protein to another. The components described in the context of these three pathways recur in many other signal-transduction pathways; bear in mind that the specific examples are representative of many such pathways.