Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 590 (GPCR) G protein coupled receptor Heterotrimeric G protein 14.1 Introduction All cells, from prokaryotes through plants and animals, sense and react to stimuli in their environments with stereotyped responses that allow them to survive, adapt, and function in ways appropriate to the needs of the organism. These responses are not simply direct physical or metabolic consequences of changes in the local environment. Rather, cells express arrays of sensing proteins, or receptors, that recognize specific extracellular stimuli. In response to these stimuli, receptors regulate the activities of diverse intracellular regulatory proteins that in turn initiate appropriate responses by the cell. The process of sensing external stimuli and conveying the inherent information to intracellular targets is referred to as cellular signal transduction. Cells respond to all sorts of stimuli. Microbes respond to nutrients, toxins, heat, light, and chemical signals secreted by other microbes. Cells in multicellular organisms express receptors specific for hormones, neurotransmitters, autocrine and paracrine agents (hormonelike compounds from the secreting cell or cells Overview of major receptor types in a cell Receptor protein kinase Ion channel Transcription factor Twocomponent complex ( Sensor Histidine kinase Response regulator NUCLEUS Transmembrane scaffold ( E1 E2 E1 E2 Guanylyl cyclase FIGURE 14.1 Receptors form a rather small number of families that share common mechanisms of action and overall similar structures. nearby), odors, molecules that regulate growth or differentiation, and proteins on the outside of adjacent cells. A mammalian cell typically expresses about fifty distinct receptors that sense different inputs, and, overall, mammals express several thousand receptors. Despite the diversity of cellular lifestyles and the enormous number of substances sensed by different cells, the general classes of proteins and mechanisms involved in signal transduction are conserved throughout living cells, as shown in FIGURE 14.1. • G protein-coupled receptors, composed of seven membrane-spanning helices, promote activation of heterotrimeric GTP-binding proteins called G proteins, which associate with the inner face of the plasma membrane and convey signals to multiple intracellular proteins. • Receptor protein kinases are often dimers of single membrane-spanning proteins that phosphorylate their intracellular substrates and, thus, change the shape and function of the target proteins. These protein kinases frequently contain protein interaction domains that organize complexes of signaling proteins on the inner surface of the plasma membrane. • Phosphoprotein phosphatases reverse the effect of protein kinases by removing the phosphoryl groups added by protein kinases. • Other single membrane-spanning enzymes, such as guanylyl cyclase, have an overall architecture similar to the receptor protein kinases but different enzymatic activities. Guanylyl cyclase catalyzes the conversion of GTP to 3′:5′- cyclic GMP, which is used to propagate the signal. • Ion channel receptors, although diverse in detailed structure, are usually oligomers of subunits that each contain several membrane-spanning segments. The subunits change their conformations and relative orientations to permit ion flux through a central pore. • Two-component systems may either be membrane spanning or cytosolic. The number of their subunits is also variable, but each two-component system contains a histidine kinase domain or subunit that is regulated by a signaling molecule and a response regulator that 590 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 591 contains a phosphorylatable aspartate (Asp) residue. • Some receptors are transmembrane scaffolds that change either the conformation or oligomerization of their intracellular scaffold domains in response to extracellular signaling molecules, or ligands, and, thus, recruit interacting regulatory proteins to a common site on the membrane. • Nuclear receptors are transcription factors, often heterodimers, that may reside in the cytoplasm until activated by agonists or may be permanently located in the nucleus. The biochemical processes of signal transduction are strikingly similar among cells. Bacteria, fungi, plants, and animals use similar proteins and multiprotein modules to detect and process signals. For example, evolutionarily conserved heterotrimeric G proteins and G protein-coupled receptors are found in plants, fungi, and animals. Similarly, 3′:5′ cyclic AMP (cAMP) is an intracellular signaling molecule in bacteria, fungi, and animals; and Ca2+ serves a similar role in all eukaryotes. Protein kinases and phosphoprotein phosphatases are used to regulate enzymes in all cells. Although the basic biochemical components and processes of signal transduction are conserved and reused, they are often used in wildly divergent patterns and for many different physiological purposes. For example, cAMP is synthesized by distantly related enzymes in bacteria, fungi, and animals, and acts on different proteins in each organism; it is a pheromone in some slime molds. Cells often use the same series of signaling proteins to regulate a given process, such as transcription, ion transport, locomotion, and metabolism. Such signaling pathways are assembled into signaling networks to allow the cell to coordinate its responses to multiple inputs with its ongoing functions. It is now possible to discern conserved reaction sequences in and between pathways in signaling networks that are analogous to devices within the circuits of analog computers: amplifiers, logic gates, feedback and feed-forward controls, and memory. This chapter discusses the principles and strategies of cellular signaling first and then discusses the conserved biochemical components and reactions of signaling pathways and how these principles are applied. 14.2 Cellular signaling is primarily chemical Key concepts • Cells can detect both chemical and physical signals. • Physical signals are generally converted to chemical signals at the level of the receptor. Most signals sensed by cells are chemical, and, when physical signals are sensed, they are generally detected as chemical changes at the level of the receptor. For example, the visual photoreceptor rhodopsin is composed of the protein opsin, which binds to a second component, the colored vitamin A derivative cis-retinal (the chromophore). When cis-retinal absorbs a photon, it photoisomerizes to trans-retinal, which is an activating ligand of the opsin protein. (For more on rhodopsin signaling see 14.20 G protein signaling modules are widely used and highly adaptable). Similarly, plants sense red and blue light using the photosensory proteins phytochrome and cryptochrome, which detect photons that are absorbed by their tetrapyrrole or flavin chromophores. Cryptochrome homologs are also expressed in animals, where they probably mediate adjustment of the diurnal cycle. A few receptors do respond directly to physical inputs. Pressure-sensing channels, which exist in one form or another in all organisms, mediate responses to pressure or shear by changing their ionic conductance. In mammals, hearing is mediated indirectly by a mechanically operated channel in the hair cell of the inner ear. The extracellular domain of a protein called cadherin is pulled in response to acoustic vibration, generating the force that opens the channel. Cells sense mechanical strain through a number of cell surface proteins, including integrins. Integrins provide signals to cells based on their attachment to other cells and to molecular complexes in the external milieu. One major group of physically responsive receptors is made up of channels that sense electric fields. Another interesting group are heat/pain-sensing ion channels; several of these heat-sensitive ion channels also respond to chemical compounds, such as capsaicin, the “hot” lipid irritant in hot peppers. Whether a signal is physical or chemical, the receptor initiates the reactions that change the behavior of the cell. We will discuss how these effects are generated in the rest of the chapter. 14.2 Cellular signaling is primarily chemical 591
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Principles of cell signaling - UT Southwestern

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