Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 602 multifunctional because their modular interaction domains and motifs are not as highly specific. Adaptors bind to two or more other signaling proteins via their protein-protein interaction domains to colocalize them or to facilitate additional interactions. Grb2 is a prototypical adaptor protein that was identified as a protein that bound to the C- terminal region of the EGF receptor. Grb2 has one SH2 and two SH3 domains. It binds constitutively to specific proline-rich segments of proteins through its SH3 domain, although this binding can be negatively regulated. One target of Grb2 is SOS, a guanine nucleotide exchange factor that activates the small GTP-binding protein Ras in response to EGF signaling. Through its SH2 domain, Grb2 binds Tyr-phosphorylated proteins, including the receptors themselves in a stimulus-dependent manner. Thus, Tyr phosphorylation of these receptors in response to ligand will enable the binding of Grb2 to the receptors, which, in turn, will recruit SOS to the membrane-localized receptor. Once at the membrane, SOS can activate its target, Ras. 14.10 Cellular signaling is remarkably adaptive Key concepts • Sensitivity of signaling pathways is regulated to allow responses to change over a wide range of signal strengths. • Feedback mechanisms execute this function in all signaling pathways. • Most pathways contain multiple adaptive feedback loops to cope with signals of various strengths and durations. A universal property of cellular signaling pathways is adaptation to the incoming signal. Cells continuously adjust their sensitivity to signals to maintain their ability to detect changes in input. Typically, when a cell is exposed to a new input, it initiates a process of desensitization that dampens the cellular response to a new plateau lower than the initial peak response, as illustrated in FIGURE 14.10. When the stimulus is removed, the desensitized state can persist, with sensitivity slowly returning to normal. Similarly, the removal of a tonic stimulus can hypersensitize signaling systems. FIGURE 14.10 Top: Upon exposure to a stimulus, signaling pathways adjust their sensitivities to adapt to the new level of input. Thus, the response decays after initial stimulation. A second similar stimulus will elicit a smaller response unless adequate time is allowed for recovery. Bottom: Some adaptation mechanisms feed back only on the receptor that is stimulated and do not alter parallel pathways. Such mechanisms are referred to as homologous. At left, agonist a for receptor R1 can initiate either of two feedback events that desensitize R1 alone. In other cases, a stimulus will also cause parallel or related systems to desensitize. At the right, agonist a initiates desensitization of both R1 and R2. The response to agonist b, which binds to R2, is also desensitized. Such heterologous desensitization is common. K a Homologous desensitization Initial response R1 R 2 R1 R 2 X 1 X 2 R esponse Response Patterns of adaptation in signaling networks Agonist a for R1 Agonist Agonist Agonist Reapply a or b Desensitization b a a R1 R 2 X 1 X 2 Time Heterologous desensitization Response R1 Agonist a for R1 or R1 R 2 Reapply a or b Y Time Y Time Z Z 602 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 603 Adaptation in signaling is one of the best examples of biological homeostasis. The adaptability of cellular signaling can be quite impressive. Cells commonly regulate their sensitivity to physiological stimuli over more than a 100-fold range, and the mammalian visual response can adapt to incoming light over a 107-fold range. This remarkable ability allows a photoreceptor cell to detect a single photon, and allows a person to read in both very dim light and intense sunlight. Adaptability is observed in bacteria, plants, fungi, and animals. Many of its properties are conserved throughout biology, although the most complex adaptive mechanisms are found in animals. The general mechanism for adaptation is the negative feedback loop, which biochemically samples the signal and controls the adaptive process. Adaptation varies with both the intensity and the duration of the incoming signal. Stronger or more persistent inputs tend to drive greater adaptive change and, often, adaptation that persists for a longer time. Cells can modulate adaptation in this way because adaptation is exerted by a succession of independent mechanisms, each with its own sensitivity and kinetic parameters. G protein pathways offer excellent examples of adaptation. FIGURE 14.11 shows that the earliest step in adaptation is receptor phosphorylation, which is catalyzed by G protein-coupled receptor kinases (GRKs) that selectively recognize the receptor’s ligand-activated conformation. Phosphorylation inhibits the receptor’s ability to stimulate G protein activation and also promotes binding of arrestin, a protein that further inhibits G protein activation. Moreover, arrestin binding primes receptors for endocytosis, which removes them from the cell surface. Endocytosis can also be the first step in receptor proteolysis. Along with these direct effects, many receptor genes display feedback inhibition of transcription, such that signaling by a receptor decreases its own expression. Stimulation thus causes multiple adaptive processes that range from immediate (phosphorylation, arrestin binding) through delayed (transcriptional regulation), and include both reversible and irreversible events. This array of adaptive events has been demonstrated for many G protein-coupled receptors, and many cells may use all of them to control output from one receptor. The speed, extent, and reversibility of adaptation are selected by a cell’s developmental program. Cells can change their patterns of adaptation both qualitatively and quantitatively by altering the points in a pathway where feedback is initiated and exerted. In a linear pathway, changing Multiple adaptation processes occur after a stimulus Relative response Receptor phosphorylation Arrestin binding Receptor endocytosis Endosomal receptor degradation 5 Receptor transcription inhibited 0 1 10 100 1000 Time (seconds) Agonist added Agonist binds 1 2 Agonist GPCR G protein Receptor recycling Lysosome 3 G protein active 4 EFFECTORS CYTOPLASM 4 Receptor degradation DNA GRK 1 Receptor Arrestin phosphorylation 2 Arrestin binding NUCLEUS Early endosome GPCR gene 3 Receptor endocytosis 5 Receptor transcription inhibited FIGURE 14.11 Multiple adaptation processes are invoked during a stimulus, and multiple nested mechanisms for adaptation are the rule. They are usually invoked sequentially according to the duration and intensity of the stimulus. For GPCRs, at least five desensitizing mechanisms are known, with others acting on the G protein and effectors. these points will alter the kinetics or extent of adaptation (Figure 14.10). In branched pathways, changing these points can determine whether adaptation is unique to one input or is exerted for many similar inputs. If receptor activation triggers its desensitization directly, or if an event downstream on an unbranched pathway triggers desensitization, then only signals that initiate with that receptor will be altered. Receptor-selective adaptation is referred to as homologous adaptation (Figure 14.10). 14.10 Cellular signaling is remarkably adaptive 603
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Principles of cell signaling - UT Southwestern

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