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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Chapter 15Signal-Transduction Pathways: An Introduction to Information Metabolism

A cell is highly responsive to specific chemicals in its environment. Hormones are chemical signals that tell a cell to respond to a change in conditions. Molecules in food or aromas communicate taste and smell through their interaction with specialized sensory cells. This chapter provides an overview of information metabolism—how cells receive, process, and respond to information from the environment. The results of genome-sequencing efforts have underscored how widespread and diverse these information-processing circuits are. For example, approximately half of the 25 largest protein families encoded by the human genome deal primarily with information processing.

Signal-transduction cascades mediate the sensing and processing of stimuli. These molecular circuits detect, amplify, and integrate diverse external signals to generate responses such as changes in enzyme activity, gene expression, or ion-channel activity. This chapter is an introduction to some of the most important classes of molecules that participate in common signal-transduction pathways. We will encounter many specific pathways in their biochemical contexts in later chapters. In this chapter, we will also consider the consequences of defects in these pathways, particularly those leading to cancer.

15.0.1. Signal Transduction Depends on Molecular Circuits: An Overview:

Signal-transduction pathways follow a broadly similar course that can be viewed as a molecular circuit (Figure 15.1). We begin by examining the challenges posed by transferring extracellular information to a cell's interior.

Figure 15.1. Principles of Signal Transduction.

Figure 15.1

Principles of Signal Transduction. An environmental signal, such as a hormone, 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 (more...)

1.

Membrane receptors transfer information from the environment to the cell's interior. A few nonpolar signal molecules such as estrogens and other steroid hormones are able to diffuse through the cell membranes and, hence, enter the cell. Once inside the cell, these molecules can bind to proteins that interact directly with DNA and modulate gene transcription. Thus, a chemical signal enters the cell and directly alters gene-expression patterns. These important signaling systems will be discussed in Chapter 31. However, most signal molecules are too large and too polar to pass through the membrane, and no appropriate transport systems are present. Thus, the information that signal molecules are present must be transmitted across the cell membrane without the molecules themselves entering the cell. A membrane-associated receptor protein often performs the function of information transfer across the membrane.

Image ch15fu2.jpg

Such a receptor is an intrinsic membrane protein that has both extracellular and intracellular domains. A binding site on the extracellular domain 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, including the intracellular domain. These structural changes are not sufficient to yield an appropriate response, because they are restricted to a small number of receptor molecules in the cell membrane. The information embodied by the presence of the ligand, often called the primary messenger, must be transduced into other forms that can alter the biochemistry of the cell.

2.

Second messengers relay information from the receptor-ligand complex. Changes in the concentration of small molecules, called second messengers, constitute the next step in the molecular information circuit. Particularly important second messengers include cyclic AMP and cyclic GMP, calcium ion, inositol 1,4,5-trisphosphate, (IP3), and diacylglycerol (DAG; Figure 15.2).

The use of second messengers has several consequences. First, second messengers are often free to diffuse to other compartments of the cell, such as the nucleus, where they can influence gene expression and other processes. Second, the signal may be amplified significantly in the generation of second messengers. Enzymes or membrane channels are almost always activated in second-messenger generation; each activated macromolecule can lead to the generation of many second messengers within the cell. Thus, a low concentration of signal in the environment, even as little as a single molecule, can yield a large intracellular signal and response. 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 affect the concentrations of common second messengers. Cross talk permits more finely tuned regulation of cell activity than would the action of individual independent pathways. However, inappropriate cross talk can cause second messengers to be misinterpreted.

3.

Protein phosphorylation is a common means of information transfer. Many second messengers elicit responses by activating protein kinases. These enzymes transfer phosphoryl groups from ATP to specific serine, threonine, and tyrosine residues in proteins.

Image ch15fu3.jpg

We previously encountered the cAMP-dependent protein kinase in Section 10.4.2. This protein kinase and others are the link that transduces changes in the concentrations of free second messengers into changes in the covalent structures of proteins. Although these changes are less transient than the changes in secondary-messenger concentrations, protein phosphorylation is not irreversible. Indeed, protein phosphatases are enzymes that hydrolytically remove specific phosphoryl groups from modified proteins.

4.

The signal is terminated. Protein phosphatases are one mechanism for the termination of a signaling process. After a signaling process has been initiated and the information has been transduced to affect other cellular processes, the signaling processes must be terminated. Without such termination, cells lose their responsiveness to new signals. Moreover, signaling processes that fail to be terminated properly may lead to uncontrolled cell growth and the possibility of cancer.

Essentially every biochemical process presented in the remainder of this book either is a component of a signal-transduction pathway or can be affected by one. As we shall see, the use of protein modules in various combinations is a clear, even dominant, theme in the construction of signal-transduction proteins. Signal-transduction proteins have evolved by the addition of such ancillary modules to core domains to facilitate interactions with other proteins or cell membranes. By controlling which proteins interact with one another, these modules play important roles in determining the wiring diagrams for signal-transduction circuits.

We begin by considering the largest and one of the most important classes of receptor, the seven-transmembrane-helix receptors.

Figure 15.2. Common Second Messengers.

Figure 15.2

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.

Molecular switches.

Figure

Molecular switches. 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 are G proteins (right), which transmit (more...)

Contents

15.1 Seven-Transmembrane-Helix Receptors Change Conformation in Response to Ligand Binding and Activate G Proteins

15.2 The Hydrolysis of Phosphatidyl Inositol Bisphosphate by Phospholipase C Generates Two Messengers

15.3 Calcium Ion Is a Ubiquitous Cytosolic Messenger

15.4 Some Receptors Dimerize in Response to Ligand Binding and Signal by Cross-phosphorylation

15.5 Defects in Signaling Pathways Can Lead to Cancer and Other Diseases

15.6 Recurring Features of Signal-Transduction Pathways Reveal Evolutionary Relationships

Summary

Problems

Selected Readings

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK21205

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