Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 636 CD3 Ligand Receptor Adaptor/ subunit Transducer Kinase cascade Transcription factor complex TCR MHC Antigen ITAM CD3 Receptor signaling pathways Growth PDGF Insulin hormone IL-1β TGF-β PDGF receptor SHP2/Grb2 SOS/Ras MAPK Ternary complex factors Insulin receptor IRS1 PI 3-kinase Akt2 FOXO GH receptor STATs T cell receptor signaling Lck After binding of the TCR to the MHC-antigen complex, Lck phosphorylates ITAMS IL-1β receptor gp130 STATs TGF-β type II receptor Type I receptor SMADs FIGURE 14.43 Major signaling cascades controlled by PDGF, insulin, TGF-, IL- 1, and growth hormone are compared. Each receptor either contains or interacts with a protein kinase that associates with or recruits a transducer. The transducer regulates downstream effectors either directly or through an intermediate protein kinase cascade. The effectors shown are transcriptional regulators. Phosphorylation by the transducer or kinase cascade activates all of the effectors except the FOXO proteins, which may be excluded from the nucleus by phosphorylation. The table only shows snapshots of much more complex signaling networks controlled by these ligands. Many of these and other intermediates serve multiple ligands. For example, IRS proteins also contribute to growth hormone and IL-1 signaling, and MAPK pathways are regulated by all of these ligands. ZAP-70 FIGURE 14.44 The T cell receptor (TCR) is a multisubunit receptor. It is phosphorylated on activation motifs or ITAMs by Lck, or a related Src family protein kinase. The phosphorylated residues create binding sites for another tyrosine protein kinase ZAP-70. ZAP-70 then recruits other signaling molecules to the complex including phospholipase C, PI 3-kinase, and a Ras exchange factor to activate downstream signaling pathways. JAK JAK Unlike many cytokine receptors in this class, the CNTF receptor does not itself span the membrane. Instead, it is glycosyl phosphoinositol (GPI)-linked to the outer face of the plasma membrane. The GPI linkage is a covalent bond, and the receptor can be released into the extracellular fluid by a specific phospholipase. The freed receptor may interact with membranes of other cells to induce signals. The use of a common signal transducing subunit, gp130, suggests that unique mechanisms exist to create ligand-specific responses; under some circumstances competition by the ligand binding subunits for interaction with the gp130 signal transducer may influence signaling outcomes. FIGURE 14.43 illustrates some parallels in signaling pathways initiated by receptors with associated or intrinsic protein kinases. The last receptor type we will discuss takes the concept of the specific and common subunits even further. The complex multiprotein T cell receptor (TCR) is found uniquely on T lymphocytes and is responsible for the ability of these cells to recognize and respond to specific antigens. The TCR, illustrated in FIGURE 14.44, is composed of eight subunits that can be described as an assembly of four dimers, αβ, γε, δε, and ζζ. The specificity of antigen recognition is determined by the α and β subunits, which are different for each cell. The remaining subunits are invariant in TCRs. The CD3 complex γ, δ, and ε subunits are similar in sequence to one another. The ζ chain, unlike the other subunits, appears on certain other cell types and may be a component of other receptors, such as the Fc receptor, which binds a portion of certain immunoglobulins. A motif called the immunoreceptor tyrosine-based activation motif, or ITAM, which features closely spaced pairs of Tyr residues, is key to signaling by the TCR. The CD3 subunits each contain one ITAM and the ζ chain contains three ITAMs, for a total of ten motifs in each TCR. Engagement of the TCR causes the Src family kinases Lck and Fyn to phosphorylate the pairs of Tyr residues in the ITAMs. The ITAMs then bind the tandem SH2 domains of the protein tyrosine kinase ζ-chain-associated protein of 70 kDa (ZAP-70), which becomes activated by Src. Tyr phosphorylation sites on ZAP-70 bind to other adaptors and signaling molecules, and Tyr phosphorylation by ZAP-70 activates additional signal transducers. The sum of these events leads to the downstream responses of T cells to antigen engagement, which include cell cycle progression and the elaboration of cytokines such as interleukin-2. 636 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 637 14.35 What’s next? New signaling proteins and new regulatory interactions seem to show up every day. The challenge now is to understand how cells organize these proteins and their individual interactions to create adaptable information-processing networks. How do cells use simple chemical reactions to sort and integrate multiple simultaneous inputs and then direct this information to diverse effector machinery? How do they interpret the inputs in the context of their growth and metabolic activities? In principle, three areas of research have to contribute to allow us to understand integrative cellular signaling. First, we need real-time, noninterfering biosensors to measure intracellular signaling reactions. Most current sensors use combinations of fluorescent moieties and signal-binding protein domains to provide fast optical readouts. For many pathways, several reactions can be monitored within cells over subsecond time scales. We need more, better, and faster sensors and sensors that can report with singlecell and subcellular resolution. Genetically encoded sensors will be complemented by synthetic molecules. Our ability to manipulate signaling networks is also improving dramatically but still falls short. We can manipulate signaling networks by overexpression, knockout, and knockdown of genes, but signaling pathways are wonderfully adaptive and frequently circumvent our best efforts to control them. We still need chemical regulators that can act promptly in cells. Structure-based design of such regulatory molecules will be vital. Last, our ability to analyze the behavior of signaling networks depends on our ability to measure and interpret signaling quantitatively. It is ironic but true that really complex systems cannot be described without explicit quantitative models for how they work. Computational modeling and simulation of signaling networks requires both better theoretical understanding of network dynamics and better algorithmic implementation. The goal is to understand how cells think. 14.36 Summary Signal transduction encompasses mechanisms used by all cells to sense and react to stimuli in their environment. Cells express receptors that recognize specific extracellular stimuli, including nutrients, hormones, neurotransmitters, and other cells. Upon receptor binding, signals are converted to well-defined intracellular chemical or physical reactions that change the activities and the organization of protein complexes within cells. The changes directed by the stimuli lead to altered cell behavior. The behavior of the cell is determined then by its intracellular state and the integrated information from extracellular stimuli so that the appropriate responses are achieved. The basic biochemical components and processes of signal transduction are conserved throughout biology. Families of proteins are used in a variety of ways for many different physiological purposes. Cells often use the same series of signaling proteins to regulate multiple processes, such as transcription, ion transport, locomotion, and metabolism. 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. References 14.1 Introduction Review Sauro, H. M. and Kholodenko, B. N., 2004. Quantitative analysis of signaling networks. Prog. Biophys. Mol. Biol. v. 86 p. 5–43. Research Milo, R., Shen-Orr, S., Itzkovitz, S., Kashtan, N., Chklovskii, D., and Alon, U., 2002. Network motifs: simple building blocks of complex networks. Science v. 298 p. 824–827. 14.2 Cellular signaling is primarily chemical Review Arshavsky, V. Y., Lamb, T. D., and Pugh, E. N., Jr., 2002. G proteins and phototransduction. Annu. Rev. Physiol. v. 64 p. 153–187. Caterina, M. J. and Julius, D., 2001. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. v. 24 p. 487–517. Gillespie, P. G. and Cyr, J. L., 2004. Myosin- 1c, the hair cell’s adaptation motor. Annu. Rev. Physiol. v. 66 p. 521–545. References 637
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Principles of cell signaling - UT Southwestern

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