12.1 General Features of Signal Transduction in Chapter 12 Biochemical Signaling

12.1 General Features of Signal Transduction

Signal transductions are remarkably specific and exquisitely sensitive. Specificity is achieved by precise molecular complementarity between the signal and receptor molecules (Fig. 12-1a), mediated by the same kinds of weak (noncovalent) forces that mediate enzyme-substrate and antigen-antibody interactions. Multicellular organisms have an additional level of specificity, because the receptors for a given signal, or the intracellular targets of a given signal pathway, are present only in certain cell types. Thyrotropin-releasing hormone, for example, triggers responses in the cells of the anterior pituitary but not in hepatocytes, which lack receptors for this hormone. Epinephrine alters glycogen metabolism in hepatocytes but not in adipocytes; in this case, both cell types have receptors for the hormone, but whereas hepatocytes contain glycogen and the glycogen-metabolizing enzyme that is stimulated by epinephrine, adipocytes contain neither.

An eight-part figure shows eight signal-transducing systems: specificity, sensitivity, amplification, modularity, desensitization or adaptation, integration, divergence, and localized response. — FIGURE 12-1 Eight features of signal-transducing systems.

Part a is labeled Specificity: Text reads, Signaling ligand fits binding site on its complementary receptor; other ligands do not fit. The image shows a rectangular receptor molecule with an irregular opening on its top side. A small irregular piece labeled L subscript 1 has an arrow pointing to the irregular opening, showing that it fits into the opening to complete the rectangle. A second small irregular piece labeled L subscript 2 has a different shape that does not fit into the opening in the rectangle and an arrow with a break in it pointing to the space. An arrow points down from the receptor to the word response. Part b is labeled Sensitivity: Text reads, Receptor has high affinity (low K subscript a) for signaling ligand (L). A similar rectangular piece is shown beneath an irregular piece labeled L that fits into an opening in its upper side. Right- and left-pointing arrows show that the two pieces fit together. The right-pointing arrow is longer than the left-pointing arrow. Part c is labeled Amplification: Text reads, When enzymes activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade. An arrow points down from the word signal to a green circle enclosing a green triangle on top of a rectangle labeled enzyme 1. Three arrows point down from enzyme 1. The left-hand arrow points to a green circle enclosing a green triangle above a rectangle labeled enzyme 2, from which three arrows point down to three green circles enclosing green triangles above three squares labeled enzyme 3. The middle and right-hand arrows similarly point down to green circles enclosing green triangles above enzyme 2 rectangles that each have three arrows pointing down to three green circles enclosing green triangles above three squares labeled enzyme 3. Part d is labeled Modularity: Text reads, Proteins with multivalent affinities form diverse signaling complexes from interchangeable parts. Phosphorylation provides reversible points of interaction. An arrow points down from the word signal to a yellow circle with yellow circles connected by short lines to its upper left and upper right and by a shorter line to P in a circle below. P in a circle is within a circular opening in the top of an oval that has a short line down to P in a circle below within a circular opening in the top of a rectangle. An arrow points down to the word response. Part e is labeled Desensitization or Adaptation: Text reads, Receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface. An arrow points down from the word signal to a green circle enclosing a green triangle above a rectangle labeled receptor. An arrow pointing down from the receptor splits so that one half indicates response below and the other circles around to a red circle with a red “X” on the left side of the receptor. Part f is labeled Integration: Text reads, When two signals have opposite effects on a metabolic characteristic such as the concentration of a second messenger X, or the membrane potential V subscript m, the regulatory outcome results from the integrated input from both receptors. Signal 1 on the left has an arrow pointing down to a green circle enclosing a green triangle above a rectangle labeled receptor 1. An arrow points down to text reading, upward arrow symbol [X] or upward arrow symbol V subscript m. Signal 2 on the right has an arrow pointing down to a green circle enclosing a green triangle above an oval labeled receptor 1. An arrow points down to text reading, downward arrow symbol [X] or downward arrow symbol V subscript m. Beneath the text showing changes in concentration in X or in V subscript m, there is a bracket labeled net Greek letter delta [X] or Greek letter delta V subscript m with an arrow pointing down to the word response. Part g is labeled Divergence: Text reads, When a receptor is activated by a signal, it activates two or more pathways with different end effects. An arrow points down from the word signal to a green circle enclosing a green triangle above a rectangle labeled receptor with two arrows pointing down from it, one to the lower left and one to the lower right. The left-hand arrow points to pathway 1, from which an arrow points down to response 1. The right-hand arrow points down to pathway 2, from which an arrow points down to response 2. Part h is labeled Localized response: Text reads, When the enzyme that destroys an intracellular message is clustered with the message producer, the message is degraded before it can diffuse to distant points, so the response is only local and brief. An arrow points down from the word signal to a green circle enclosing a green triangle above a rectangle labeled receptor. A horizontal line runs through the center of the receptor and through the center of an oval to its right labeled message remover. An arrow points down from receptor and then bends right to the word message. A curved arrow runs from the word message up to the bottom of the message removal oval, then down to the word message with a red “X” across it. Text below reads, response (local).

Signal-Transducing Systems Share Common Features

The extraordinary sensitivity of signal transduction results from the high affinity of signal receptors for their ligands (Fig. 12-1b). This affinity can be expressed as the dissociation constant, $K_{d}$ $upper K Subscript d$ , for the receptor-ligand interaction. $K_{d}$ $upper K Subscript d$ is commonly $10^{- 7} M$ $10 Superscript negative 7 Baseline upper M$ or less, meaning that the receptor detects micromolar to nanomolar concentrations of a signaling ligand. In some cases, cooperativity in receptor-ligand interactions results in relatively large changes in receptor activation with small changes in ligand concentration, further increasing the sensitivity of signal detection.

Amplification results when an enzyme is activated by a signal receptor and, in turn, catalyzes the activation of many molecules of a second enzyme, each of which activates many molecules of a third enzyme and so on, in an enzyme cascade (Fig. 12-1c). Such cascades can produce amplifications of several orders of magnitude within milliseconds. The response to a signal must also be terminated, such that the downstream effects are in proportion to the strength of the original stimulus.

Interacting signaling proteins are modular. Many signaling proteins have multiple domains that recognize specific features in several other proteins, or in the cytoskeleton or plasma membrane. This modularity allows a cell to mix and match a set of signaling molecules to create a wide variety of multienzyme complexes with different functions or cellular locations. One common theme in these interactions is the binding of one modular signaling protein to phosphorylated residues in another protein; the resulting interaction can be regulated by phosphorylation or dephosphorylation of the protein partner (Fig. 12-1d). Nonenzymatic scaffold proteins with affinity for several enzymes that interact in cascades bring these enzymes together, ensuring that they interact at specific cellular locations and at specific times. Many of the regions involved in protein-protein interactions are intrinsically disordered (see Fig. 4-20), capable of folding differently depending on which protein they interact with. As a result, a single protein can have multiple functions in signaling pathways.

The sensitivity of receptor systems is subject to modification. When a signal is present continuously, the receptor system becomes desensitized (Fig. 12-1e), so that it no longer responds to the signal. When the stimulus falls below a certain threshold, the system again becomes sensitive. Think of what happens to your visual transduction system when you walk from bright sunlight into a darkened room or from darkness into the light.

Signal integration (Fig. 12-1f) is the ability of the system to receive multiple signals and produce a unified response appropriate to the combined needs of the cell or organism. Different signaling pathways converse with each other at several levels, generating complex cross talk that maintains homeostasis in the cell and the organism.

Signaling pathways are often divergent — branched rather than linear; one stimulus acts through one receptor, which activates two or more pathways with different downstream targets and responses (Fig. 12-1g).

A final noteworthy feature of signal-transducing systems is response localization within a cell (Fig. 12-1h). When the components of a signaling system are confined to a specific subcellular structure (a raft in the plasma membrane, for example), a cell can regulate a process locally, without affecting distant regions of the cell.

One of the revelations of research on signaling is the remarkable degree to which signaling mechanisms have been conserved during evolution. Although the number of different biological signals to which cells respond is probably in the thousands (Table 12-1 lists a few important types), and the kinds of responses elicited by these signals are comparably numerous, the machinery for transducing all of these signals is built from about 10 basic types of protein components (Table 12-2).

TABLE 12-1 Some Signals to Which Cells Respond
Antigens	Mechanical touch
Cell surface glycoproteins, oligosaccharides	Microbial, insect pathogens
Developmental signals	Neurotransmitters
Extracellular matrix components	Nutrients
Growth factors	Odorants
Hormones	Pheromones
Hypoxia	Tastants
Light

TABLE 12-2 Some Conserved Elements of Animal Signaling Systems
Plasma membrane receptors with 7 transmembrane (7tm) helices
G proteins that bind GTP or GDP and interface with membrane receptors
Membrane enzymes with cyclic nucleotides as substrates or products
Protein kinases that phosphorylate GPCR receptors
Membrane protein tyrosine kinases
Cyclic nucleotide–dependent protein kinases
${Ca}^{2 +}$ $Ca Superscript 2 plus$ -binding proteins
${Ca}^{2 +}$ $Ca Superscript 2 plus$ -dependent protein kinases
Protein kinases that are activated during cell division
Nonenzymic protein scaffolds that bring modules together

The General Process of Signal Transduction in Animals Is Universal

In this chapter we consider the molecular details of several representative signal-transduction systems, classified according to the type of receptor. The trigger for each system is different, but the general features of signal transduction are common to all: a signal (ligand) interacts with a receptor; the activated receptor interacts with cellular machinery, producing a second signal or a change in the activity of a cellular protein; the metabolic activity of the target cell undergoes a change; and finally, the transduction event ends. To illustrate these general features of signaling systems, we will look at examples of four basic receptor types (Fig. 12-2).

G protein–coupled receptors that indirectly activate (through GTP-binding proteins, or G proteins) enzymes that generate intracellular second messengers. Examples include the β-adrenergic receptor system that responds to epinephrine (Section 12.2) and the vision, olfaction, and gustation systems (Section 12.3).
Receptor enzymes in the plasma membrane that have an enzymatic activity on the cytoplasmic side, triggered by ligand binding on the extracellular side. Receptors with tyrosine kinase activity, for example, catalyze the phosphorylation of Tyr residues in specific intracellular target proteins. Examples include the insulin receptor (Section 12.4) and receptor guanylyl cyclases (see Box 12-2).
Gated ion channels of the plasma membrane that open and close (hence the term “gated”) in response to the binding of chemical ligands or changes in transmembrane potential. These are the simplest signal transducers (Section 12.6).
Nuclear receptors that bind specific ligands (such as the hormone estrogen) and alter the rate at which specific genes are transcribed and translated into cellular proteins. Because steroid hormones function through mechanisms intimately related to the regulation of gene expression, we consider them briefly in Section 12.7 and defer a detailed discussion of their action until Chapters 23 and 28.

A four-part figure shows four general types of signal transducers: a G protein-coupled receptor, a receptor enzyme (tyrosine kinase), a gated ion channel, and a nuclear receptor. — FIGURE 12-2 Four general types of signal transducers.

A plasma membrane extends horizontally from left to right. Text above the left side of the membrane reads, 1. G protein-coupled receptor. External ligand (L) binding to receptor (R) activates an intracellular G T P-binding protein (G), which regulates an enzyme (E n z) that generates an intracellular second messenger (X). Beneath this text, an irregular vertical rectangle labeled R extends across the plasma membrane. Right- and left-pointing arrows with a circle labeled L above show that the rectangle reversibly binds to the circle L and joins to a small, irregular protrusion at the upper left of an oval labeled G within the cell. An arrow points right to show a roughly rectangular structure labeled E n z with the top half divided into two halves and attached to the oval labeled G to the lower left with short radiating lines extending out around both the rectangle and oval and with an arrow pointing down to X within the cell. Text above the middle of the membrane reads, 2 a. Receptor enzyme (tyrosine kinase). Ligand binding activates tyrosine kinase activity by autophosphorylation. Beneath this text, two narrow vertical strands run parallel through the membrane. Each bends away from the other beneath the membrane, where it has an irregular rounded piece attached within the cell. Each also has a thicker irregular piece above the membrane that bends toward the thicker irregular piece of the other half, causing them to join together to form a rounded horizontal piece connecting the two halves. Right- and left-pointing arrows show that a circle labeled L comes in and binds reversibly to the right side of the curved horizontal piece on top, causing the two halves to change shape and move apart to look more like a letter “T”. On the bottom, the irregular rounded pieces cross over so that the right-hand one is on the left and the left-hand one is on the right. They are close together and surrounded by short radiating lines. An arrow points down to text reading, kinase cascade. Text adjacent to the words kinase cascade reads, 2 b. Kinase activates transcription factor (T), altering gene expression. An arrow points down from the words kinase cascade to a circle labeled T that has an arrow that runs through the nuclear envelope to point to a similar circle labeled T attached to the left side of a double helix of D N A. To the right of the circle labeled T, a short vertical line runs up from the D N A and bends to point to the right, where a wavy arrow to the right is labeled m R N A. A curved upward arrow from the m R N A points to protein. Text above the right side of the membrane reads, 3. Gated ion channel. Channel opens or closes in response to concentration of signal ligand or membrane potential. A long rectangular channel has long rounded rectangles on each side that bend away from the center at each end. The upper left side has a concavity beneath a circle labeled L. Right- and left-pointing arrows show that the circle labeled L reversibly binds to the upper left side of the channel, causing the two sides to move apart. The word ion above the membrane has an arrow pointing through the channel to show movement into the cell. Beneath the nuclear envelope at the bottom center of the illustration, text reads, 4. Nuclear receptor. Hormone binding allows the receptor to regulate the expression of specific genes. A circle labeled L above the plasma membrane has a dotted arrow pointing to an oval containing a circle labeled L bound to the top of a double helix of D N A. To the right of the oval, a short vertical line runs up from the D N A and bends to point to the right, where a wavy arrow to the right is labeled m R N A. A curved upward arrow from the m R N A points to protein.

As we begin this discussion of biological signaling, a word about the nomenclature of signaling proteins is in order. These proteins are typically discovered in one context and named accordingly, then prove to be involved in a broader range of biological functions for which the original name is not helpful. For example, the retinoblastoma protein, pRb, was initially identified as the product of a mutation that contributes to cancer of the retina (retinoblastoma), but it is now known to function in many pathways essential to cell division in all cells, not just those of the retina. Some genes and proteins are given noncommittal names: the tumor suppressor protein p53, for example, is a protein of 53 kDa, but its name gives no clue to its great importance in the regulation of cell division and the development of cancer. In this chapter we generally define these protein names as we encounter them, introducing the names that are commonly used by researchers in the field.

SUMMARY 12.1 General Features of Signal Transduction

All cells have specific and highly sensitive signal-transducing mechanisms, which have been conserved during evolution.
A wide variety of stimuli act through specific protein receptors in the plasma membrane.
In all types of signal transduction, receptors bind the signal ligand and initiate a process that amplifies the signal, integrates it with input from other receptors, and transmits the information throughout the cell. If the signal persists, receptor desensitization reduces or ends the response.
Multicellular organisms have four general types of signaling mechanisms: plasma membrane proteins that act through G proteins, receptors with internal enzyme activity (such as tyrosine kinase), gated ion channels, and nuclear receptors that bind steroids and alter gene expression.