Communication by extracellular signals usually involves the following steps: (1) synthesis and (2) release of the signaling molecule by the signaling cell; (3) transport of the signal to the target cell; (4) binding of the signal by a specific receptor protein leading to its activation; (5) initiation of one or more intracellular signal-transduction pathways by the activated receptor; (6) specific changes in cellular function, metabolism, or development; and (7) removal of the signal, which often terminates the cellular response (see Figure 13-1). The vast majority of receptors are activated by binding of secreted or membrane-bound molecules (e.g., hormones, growth factors, neurotransmitters, and pheromones).
Some receptors, however, are activated by changes in the concentration of a metabolite (e.g., oxygen or nutrients) or by physical stimuli (e.g., light, touch, heat). In E. coli, for instance, receptors in the cell-surface membrane trigger signaling pathways that help the cell respond to changes in the external level of phosphate and other nutrients (see Figure 4-18).
Signaling Molecules in Animals Operate over Various Distances
In animals, signaling by soluble extracellular molecules can be classified into three types—endocrine, paracrine, or autocrine—based on the distance over which the signal acts. In addition, certain membrane-bound proteins act as signals.
In endocrine signaling, the signaling molecules, called hormones, act on target cells distant from their site of synthesis by cells of the various endocrine organs. In animals, an endocrine hormone usually is carried by the blood or by other extracellular fluids from its site of release to its target.
In paracrine signaling, the signaling molecules released by a cell affect target cells only in close proximity. The conduction by a neurotransmitter of a signal from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction) occurs via paracrine signaling (Chapter 7). Many growth factors regulating development in multicellular organisms also act at short range. Some of these molecules bind tightly to the extracellular matrix, unable to signal, but subsequently can be released in an active form. Many developmentally important signals diffuse away from the signaling cell, forming a concentration gradient and inducing various cellular responses depending on their concentration at a particular target cell (Chapter 15).
In autocrine signaling, cells respond to substances that they themselves release. Some growth factors act in this fashion, and cultured cells often secrete growth factors that stimulate their own growth and proliferation. This type of signaling is particularly common in tumor cells, many of which overproduce and release growth factors that stimulate inappropriate, unregulated proliferation of themselves as well as adjacent nontumor cells; this process may lead to formation of a tumor mass.
Signaling molecules that are integral membrane proteins located on the cell surface also play an important role in development. In some cases, such membrane-bound signals on one cell bind receptors on the surface of an adjacent target cell to trigger its differentiation. In other cases, proteolytic cleavage of a membrane-bound signaling protein releases the exoplasmic region, which functions as a soluble signaling protein.
Some signaling molecules can act both short range and long range. Epinephrine, for example, functions as a neuro-transmitter (paracrine signaling) and as a systemic hormone (endocrine signaling). Another example is epidermal growth factor (EGF), which is synthesized as an integral plasmamembrane protein. Membrane-bound EGF can bind to and signal an adjacent cell by direct contact. Cleavage by an extracellular protease releases a soluble form of EGF, which can signal in either an autocrine or a paracrine manner.
Receptors Activate a Limited Number of Signaling Pathways
The number of receptors and signaling pathways that we discuss throughout this book initially may seem overwhelming. Moreover, the terminology for designating pathways can be confusing. Pathways commonly are named based on the general class of receptor involved (e.g., GPCRs, receptor tyrosine kinases), the type of ligand (e.g., TGFp, Wnt, Hedgehog), or a key intracellular signal transduction component (e.g., NF-kB). In some cases, the same pathway may be referred to by different names. Fortunately, as researchers have discovered the molecular details of more and more receptors and pathways, some principles and mechanisms are beginning to emerge. These shared features can help us make sense of the wealth of new information concerning cell-to-cell signaling.
First, external signals induce two major types of cellular responses: (1) changes in the activity or function of specific pre-existing proteins and (2) changes in the amounts of specific proteins produced by a cell, most commonly as the result of modification of transcription factors leading to activation or repression of gene transcription. In general, the first type of response occurs more rapidly than the second type. Signaling from G protein-coupled receptors, described in later sections, often results in changes in the activity of preexisting proteins, although activation of these receptors on some cells also can induce changes in gene expression.
The other classes of receptors depicted in Figure 13-1 operate primarily to modulate gene expression. In some cases, the activated receptor directly activates a transcription factor in the cytosol (e.g., TGFp and cytokine receptor pathways) or assembles an intracellular signaling complex that activates a cytosolic transcription factor (e.g., Wnt pathways). In yet other pathways, specific proteolytic cleavage of an activated cell-surface receptor or cytosolic protein releases a transcription factor (e.g., Hedgehog, Notch, and NF-kB pathways). Transcription factors activated in the cy-tosol by these pathways move into the nucleus, where they stimulate (or occasionally inhibit) transcription of specific target genes. Signaling from receptor tyrosine kinases leads to activation of several cytosolic protein kinases that translocate into the nucleus and regulate the activity of nuclear transcription factors. We consider these signaling pathways, which regulate transcription of many genes essential for cell division and for many cell differentiation processes, in the following two chapters.
Second, some classes of receptors can initiate signaling via more than one intracellular signal-transduction pathway, leading to different cellular responses. This complication is typical of G protein-coupled receptors, receptor tyrosine kinases, and cytokine receptors.
Third, despite the huge number of different kinds of lig-ands and their specific receptors, a relatively small number of signal-transduction mechanisms and highly conserved intracellular proteins play a major role in intracellular signaling pathways. Our knowledge of these common themes has advanced greatly in recent years. For instance, we can trace the entire signaling pathway from binding of ligand to receptors in several classes to the final cellular response.
Before delving into the particulars of individual signaling pathways, we discuss the basic properties of cell-surface receptors, as well as methods for identifying and studying them, in the remainder of this section; important general features of intracellular signal transduction are presented in Section 13.2.
Receptor Proteins Exhibit Ligand-Binding and Effector Specificity
The response of a cell or tissue to specific external signals is dictated by the particular receptors it possesses, by the signal-transduction pathways they activate, and by the intra-cellular processes ultimately affected. Each receptor generally binds only a single signaling molecule or a group of very
▲ EXPERIMENTAL FIGURE 13-2 Mutational studies have identified the patches of amino acids in growth hormone and its receptor that determine their highly specific mutual interaction. The outer surface of the plasma membrane Is toward the bottom of the figure, and each receptor Is anchored to the membrane by a hydrophobic membrane-spanning alpha helix that Is not shown. As determined from the three-dimensional structure of the growth hormone-growth hormone receptor complex, 28 amino acids in the hormone are at the binding interface with one receptor. Each of these amino acids was mutated, one at a time, to alanine, and the effect on receptor binding was determined. (a) From this study it was found that only eight amino acids on growth hormone (pink) contribute 85 percent of the binding energy;
closely related molecules (Figure 13-2). In contrast, many signaling molecules bind to multiple types of receptors, each of which can activate different intracellular signaling pathways and thus induce different cellular responses. For instance, different types of acetylcholine receptors are found on the surface of striated muscle cells, heart muscle cells, and pancreatic acinar cells. Release of acetylcholine from a neuron adjacent to a striated muscle cell triggers contraction by activating a ligand-gated ion channel, whereas release adjacent to a heart muscle slows the rate of contraction via activation of a G protein-coupled receptor. Release adjacent to a pancreatic acinar cell triggers exocytosis of secretory granules that contain digestive enzymes. Similarly, epinephrine binds to several different G protein-coupled receptors, each of which induces a distinct cellular response. Thus each receptor protein is characterized by binding specificity for a particular lig-and, and the resulting receptor-ligand complex exhibits effectorspecificity (i.e., mediates a specific cellular response).
On the other hand, different receptors of the same class that bind different ligands often induce the same cellular responses in a cell. In liver cells, for instance, the hormones epinephrine, glucagon, and ACTH bind to different members of the G protein-coupled receptor family, but all these these amino acids are distant In the primary sequence but adjacent In the folded protein. Similar studies showed that two tryptophan residues (blue) in the receptor contribute most of the energy for binding growth hormone, although other amino acids at the interface with the hormone (yellow) are also important. (b) Binding of growth hormone to one receptor molecule is followed by (c) binding of a second receptor to the opposing side of the hormone; this involves the same set of yellow and blue amino acids on the receptor but different residues on the hormone. As we see in the following chapter, such hormone-induced receptor dimerization is a common mechanism for receptor activation. [After B. Cunningham and J. Wells, 1993, J. Mol. Biol. 234:554, and T. Clackson and J. Wells, 1995, Science 267:383.]
receptors activate the same signal-transduction pathway, one that promotes synthesis of cyclic AMP (cAMP). This small signaling molecule in turn regulates various metabolic functions, including glycogen breakdown. As a result, all three hormones have the same effect on liver-cell metabolism.
Maximal Cellular Response to a Signaling Molecule May Not Require Activation of All Receptors
As we've seen, activation of a cell-surface receptor and subsequent signal transduction are triggered by binding of a signaling molecule (ligand) to the receptor. This binding depends on weak, noncovalent forces (i.e., ionic, van der Waals, and hydrophobic interactions) and molecular complementarity between the interacting surfaces of a receptor and ligand (Chapter 2). The specificity of a receptor refers to its ability to distinguish closely related substances. The insulin receptor, for example, binds insulin and a related hormone called insulinlike growth factor 1, but no other peptide hormones.
Ligand binding usually can be viewed as a simple reversible reaction, kon
koff which can be described by the equation
where [R] and [L] are the concentrations of free receptor and ligand, respectively, at equilibrium, and [RL] is the concentration of the receptor-ligand complex. Kd, the dissociation constant of the receptor-ligand complex, measures the affinity of the receptor for the ligand. This equilibrium binding equation can be rewritten as
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