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Cell Signaling Networks Mechanisms of Cellular Signaling Experimental Approaches to Understanding Signaling Networks Computational Approaches that Facilitate the Understanding of Intracellular Networks The Importance of Signaling Networks in Understanding Mechanisms that Underlie Disease and Drug Discovery Perspective and Future Directions
Department
of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York,
Signal transduction in cells has been an area of intense study for many years. However, until recently, the focus was on interactions between individual components rather than on the global behavior of the cell signaling networks. New experimental technologies, such as protein and DNA microarrays, high-throughput screening instrumentation, and diverse compound libraries, allow for many interactions to be examined simultaneously. Along with new experimental methods, quantitative models with mathematical methods, such as deterministic, stochastic, and statistical analyses and graph theory, have been useful in the mapping and analysis of intracellular signaling networks. Here we describe current experimental and computational approaches that are used to develop a global understanding of the complex behavior of intracellular signaling networks. We also discuss important applications of signaling network analysis, including the discovery of new drug targets, the identication of the signaling components responsible for the side (off-target) effects of drugs, and the development of combination therapies.
Currently it is estimated that the human genome contains 25,000 protein-encoding genes (1), which correspond to several hundred thousand possible protein species resulting from alternative splicing and posttranslational modications. Of these presumed protein species, the functions and interactions of only a fraction are well understood. Among the well-studied proteins, many interactions result in complex networks that often form the basis for the complex physiologic functions. Moreover, protein expression levels vary among individuals and different cell or tissue types, and the distribution of proteins varies in the subcellular regions of each cell. Therefore, it is important to develop tools to analyze these systems as a whole. Despite the growing need for global analysis of signaling networks, mapping individual pathways has been the main approach in studying signal transduction. Studies focused on dening how these pathways interact to form networks are relatively new. By mapping out signaling networks within cells, we can get an initial description of the rules that are applied in the development of these networks and the discovery of new trends or network properties. This review article discusses the interactions that comprise intracellular networks, the mechanisms
underlying them, their conserved trends, and the emerging tools being developed to understand networks as a whole.
Both authors have contributed equally and share credit as rst authors.
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
(a)
MMP EGF EGF EGF
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GPCR G PCR PC
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PKC P Gab1
PLC P Grb2 P P
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Sos1 Cell survival P Phosphate group Kinase e Adaptor or protein G-prot otein ote GTPase activator protein GTPas Phosph holipase Guanin ne nuclear n exchange h factor Phosp sphatase Ligand g Metallo oproteinase o JNK JNKK Raf Mek Rac Ras-GDP
C
Ras-GTP Raf P MAPK cascade P Mek P M P Erk Erk P Positive Feedback Loop (PFBL)
Transcription factors
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Cell cycle/proliferation Negative Feedback Loop (NFBL)
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diacyl triacyl lipopeptide lipopeptide lipopeptide opept TLR TL TLR R1 T TL TLR TLR6
LPS
flagellin
uropathogenic bacteria
ssRNA
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dsRNA
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TLR TL LR IFNA IFNAR F FN TL 5 TLR TLR5 T 9 TL TLR TLR9 TL TLR TLR1 TLR11 T L 1 T 3 TL TLR TLR3 7/8 7/8 MyD88 D88 MyD88 8 D88 88 8 PM P MyD88 MyD88 D88 8 MyD88 D88 MyD88 P P P MyD88 TRIF P MyD88 P MyD88 D88 8 JAK P P TIRAP P TIRAP P TIRAP P TIRAP P P TIRAP P P P TIRAP P TIRAP P TIRAP TL TLR TLR2 L 2 TL 4 TLR TLR4
TRAF6
STAT1 T1 1 STAT2
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P ATF2
PPP PP P P P IRF3 P P IRF3 P cJun P RF3 ATF2 P P IR A IRF3 3 P P IR IRF3 F3 3 NFkB P P P P P PP Inflammatory cytokines
IFN IFN
Figure 1 Signaling networks and loops. Schematic interaction maps that represent the major components in the signaling networks emanating from (a) the epidermal growth factor receptor and (b) the toll-like receptor are shown. (c) Schematics that represent several types of regulatory loops that are found in intracellular signaling networks.
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
p38-MAPK and JNK (cJun NH(2)-terminal kinase) (1316). A PFBL is created by PI3K activity in the EGFR pathway (represented as a thick, curved arrow in Fig. 1a). Once indirectly activated by EGFR (through phosphorylation of Gab1), PI3K generates phosphatidylinositol (35)-trisphosphate that facilitates the recruitment of additional Gab1 (17). In a larger PFBL, EGFR signaling causes the transcription of its ligands HB-EGF and TGF, through the Ras-MAPK pathway (18). A PFBL is found where the ligand, interferon (IFN), activates a TLR pathway that leads to its transcription (Fig. 1b) (19). An example of a NFBL is where SHP, a phosphatase, is recruited to EGFR through Gab1 and Grb2 but inhibits EGFR signaling by dephosporylation of the receptor (5, 20). Another example of a more distal NFBL is EGFR activation of Ras-GAP (Ras-GTPase activating protein), which inhibits Ras signaling by facilitating Ras-mediated GTP hydrolysis to GDP (5). All these regulatory mechanisms play a crucial role in maintaining signal amplication and cellular homeostasis. PFBLs amplify signal and NFBLs reduce signal, which maintains a balance. Properties of signaling networks such as redundancy and robustness have been identied through the examination of reconstructed signaling networks (21, 22). Redundancy, such as that provided by FFLs, is a mechanism of maintaining homeostasis because the same outcome can be achieved by several different paths. If one path fails, another route is available to the same outcome, which leads to network robustness.
and phospholipase-C (PLC), have afnity for the intracellular tyrosine-phosphorylated EGFR region (Fig. 1a). Many possible combinations of ligands, receptors, and recruited adaptor proteins can form the nal signaling complex. Therefore, complexity in the signaling network is introduced early, at the level of the ligand. Further, the ligand governs the nature of the dimerized receptors which, in turn, modulate the mode and magnitude of the signal. At the ligandreceptor level, the TLR network (Fig. 1b) is similar to the EGFR network with respect to ligand specicity. Some TLR ligands are specic for one TLR, and others are not. In contrast to the EGFR network, one main adaptor protein MyD88 (myeloid differentiation primary response gene 88) has similar afnity for all TLR family members, with the exception of TLR3. Therefore, in the TLR pathway the nature and magnitude of the signal depends highly on the expression level of the receptors and the nature and relative amount of ligand(s) present. Because of the variation in the identity and level of expressed receptors across various cell types, different cells will respond differently to stimulation with particular ligands. The distribution of different receptors reects the interplay of the signaling capacity of the receptor and its signicance in the specialization of the cell type. For example, immune cells, such as dendritic cells, have a relatively high expression level of TLRs, whereas epithelial cells have relatively high expression levels of growth factor receptors (25, 26).
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
was examined by Blagoev et al. (35) in a phospho-proteomics study by examining the phosphorylation pattern of EGFR after different periods of EGF treatment. The spatial aspects of signaling can be captured by analyzing different fractions of the cell such as the nucleus, organelles, vesicles, membrane-bound proteins, or cytoplasmic proteins. Several recent studies have analyzed holistically the signaling components of puried cellular organelles, such as synaptic vesicles (36) and the ER-Golgi apparatus (37).
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
Collaborative research initiatives for the use of chemical genetics to facilitate discovery of potential cancer (or other) therapeutics by the Initiative for Chemical Genetics at the National Cancer Institute (50) and to facilitate the discovery of new targets and drug candidates by the Chemical Genomics Center at the National Institutes of Health (51) have been initiated. These initiatives will result in databases that contain information that most likely will be valuable to the study of cellular signaling networks.
efforts between the two elds. The major steps involved in the development of mathematical models that yield systems-level insights are outlined in Fig. 2. The rst step in constructing a cell signaling network model is to generate an in silico interaction network. Signaling components of interest are identied, and data on binary interactions are extracted from the experimental literature. Often times, the creation of an entire interaction map for a large network is beyond the scope of one laboratory; therefore, public databases have been created in which newly discovered proteins and/or protein interactions are deposited (5763). However, often data are included from studies that cover a broad range of protein interactions, such as proteomic studies or yeast two-hybrid screens, and frequently contain many potential false positives or negatives. Thus, it becomes necessary to critically examine each reference to verify the interaction data reported, as this in silico network is the basis of further study. Once the reaction network is created, an appropriate mathematical approach is identied according to the information available and the biological question(s) to be addressed. In this section, some mathematical approaches that have been applied successfully in the analysis of biological signaling networks will be discussed. These methods are summarized in Table 1 (6485).
Statistical approaches
High-throughput experiments such as those involved with genomic and proteomic studies (e.g., microarray studies and SILAC-mass spectrometry studies, discussed in the section entitled Experimental approaches to understanding signaling networks) are useful for understanding the interdependence of signaling components in the network. However, these types of experiments generally yield large-scale data sets that often are analyzed by computational algorithms, based on statistics. The basic concept behind this computational statistical analysis is to identify clusters or groups of signaling components that show similar trends. This analysis is used to extract the relationships between different signaling components in a network from these large-scale data sets. These kinds of analyses have been used for analyzing microarray data to identify patterns that correlate with distinct physiologic and pathophysiologic states. For example, an hierarchical algorithm has been used to identify different types of cancers in human soft tissue tumors (86), and K-mean clustering has been used to identify molecular subtypes of brain tumors (87). However, these types of statistical clustering analysis do not exclude the noise or artifacts induced by the experimental techniques. To overcome this limitation, singular value decomposition (a modied type of principal component analysis) has been used to identify which clusters of signaling components have a signicant amount of inuence in changing patterns of biological behaviors (8891). Another statistical technique, partial least square regression analysis on multidimensional experiments (signaling components, time, and ligands), has been used to predict new interactions between components in a network, regulating apoptosis (92).
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
Graph theory
Statistical analysis is a powerful tool for understanding interdependence between groups of self-similar behaviors, especially when a large data set is being analyzed. However, it does not yield information about the topology of the interaction network. Graph theory-based approaches have been developed to study the topological properties of a large biological network. In graph theory, each signaling component in the network is represented as a node and identied by its degree , which represents the number of interacting partners. Within the context of the entire signaling network, the relationship between the degree of individual nodes and the degree of distribution of the whole network can be characterized. This kind of analysis has shown many intrinsic topological properties, such as scale-free conguration, small world conguration, and modular organization of networks across different cell types and species (2, 7, 22, 93, 94).
Boolean analysis
Although it is possible to analyze the topological properties of the network using graph theory, the states of the signaling components (phosphorylated/dephosphorylated, bound/unbound) often are not accounted for in such analyses. Boolean analysis can be used to understand such dynamics. In Boolean analysis, the signaling components in the network are identied by strings of 0s and 1s. The activated state of the protein is denoted by 1, and the inactivated state is denoted by 0. Changes in states of components can be computed as a function of various perturbations to the network. To illustrate the concept of Boolean analysis in a biological context, an example is taken from the TLR pathway (Fig. 1c). To initiate the induction of the IFN gene in TLR signaling pathway, it is necessary for three transcription factor complexes,
ATF2-cJun heterodimer, two IRF3 homodimers, and NF-B, to bind simultaneously at the promoter region. This biological condition can be represented in the Boolean form in the following way: Each of the four transcription factor complexes, ATF2-cJun, two IRF3 homodimers and NF-B, and the gene IFN is expressed as strings of ve 0s and 1s that lead to 25 (or 32) combinations. For instance, the representation 11111 denotes that all transcription factor complexes are bound to the promoter regions and IFN gene expression occurs; 01000 denotes that only one of two IRF3 homodimers are bound to the promoter region and, hence, IFN gene expression does not occur. A simulation is performed to analyze the effect of the change of state of an upstream signaling component on the downstream component in the signaling network, and rules, based on Boolean operators, are applied (95, 96). Boolean analysis has been used to understand the effect of different states of signaling components on their downstream signaling components under various conditions. For example, Albert and Othmer (64) used Boolean analysis of a Drosophila melanogaster network to validate results from previously published microarray data and predicted the crucial role of the two genes, wingless and sloppy paired , in segment polarity. Gonzales et al. (65) mutated different genes in silico and used Boolean analysis to predict that the delay in the activation of two genes Apterous and Notch is essential to maintain the dorsal-ventral boundary of Drosophila melanogaster . Sarkar and Franza (97) predicted that the costimulation of T-cell receptors (TCR) and CD28 in T cells inuences cell proliferation by providing a greater diversity of paths in the network. Maayan et al. (67) has used a combination of graph theory and Boolean analysis to obtain a distribution of redundant pathways in a cell signaling network.
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
Table 1 Various computational methods that have been used in analyzing signaling networks Computational methods Deterministic analysis Coupled biochemical systems Descriptions References (6470)
Reaction kinetics are represented by sets of ordinary differential equations (ODEs). Rates of activation and deactivation of signaling components are dependent on activity of upstream signaling components. Reaction kinetics and movement of signaling components are represented by partial differential equations (PDEs). Useful for studies of reactiondiffusion dynamics of signaling components in two or three dimensions.
Spatially specied systems
Stochastic analysis
Based on Monte Carlo theory and probabilities of reactions. Facilitates modeling signaling components in small volumes and capturing stochastic uctuations within the network. Describes topology of networks and subnetworks, based on quantication of the number of nodes (signaling components) and links between them. Dynamic properties of networks through Boolean analysis. Network analysis based on probabilities (Markov chain and Bayesian) to identify paths and relationships between different nodes in the network. Clustering based on correlations to identify group relationships. Partial least square regression analysis to track pathways of signal ow. Principal component analysis to identify signicant signaling components.
(7173)
Graph theory
(7581)
Statistical analysis
(8285)
Determinstic analysis
Although large-scale network analysis using graph theory or Boolean analysis can be very powerful in understanding the overall topological properties of the network, these tools do not take into consideration the rate of change of states of the signaling components with respect to time, explicitly. To understand the dynamics of activation or deactivation of a component in a signaling network, the most commonly used approach is deterministic analysis, which involves solving ordinary differential equations (ODEs). For deterministic analysis of biological systems, the initial concentrations and the kinetic parameters (KM , k cat, and Vmax ) for enzymatic reactions and binding reactions (Kd and kon or koff ) are required and need to be determined experimentally. Numerous examples exist in which deterministic analysis has provided critical insights into the dynamic behavior of a protein in a network under various conditions. One early effort in computational modeling, which uses a system of ODEs, is the EGFEGFR reaction kinetics and internalization of the 8
receptors (98102). Bhalla and Iyengar (103) predicted the importance of feedback loops in a signaling network by illustrating bistable behavior of output proteins. Moreover, the sensitivity of the MAPK activity in response to a stimulus has been studied in detail by using systems of ODEs (104, 105). Bentele et al. (106) have studied apoptosis induced by the CD95 receptor by using deterministic analysis.
Stochastic analysis
The deterministic analysis provides the average behavior of signaling components in a network but does not include the results of uctuations in the activation states of the signaling components (noise). Such analysis becomes essential when the volume of interest becomes in the scale of femtoliters because of the limitingly small number of molecules contained in such a small volume (1 fL of a 0.1 M solution is equivalent to 60 molecules). Small volumes such as these are biologically relevant and present in cellular systems quite often, for example, in the spines of dendrites and endosomal regions. Moreover,
WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
stochastic analysis becomes important in studying gene regulation where many genes have less than 10 copy numbers. Stochastic analyses, based on Monte Carlo theory and probabilities, have been used to capture the effects of uctuations of an upstream signaling component on the kinetics of a downstream signaling component in the network. The most popular method for stochastic analysis is the Gillespie method (107), which is based on the probability of which reaction will take place within a dened time period. This type of simulation can give insights into the characteristics of signaling events at the single-molecule level. For example, in the analysis of an individual cell, noise introduced in enzymatic futile cycles can be strong enough to switch the system from one state of the cell to another (108). This technique has not gained much popularity over deterministic approaches, even though it is the only appropriate mathematical representation for certain cellular phenomenon. This lack of popularity primarily is because of the following reasons: 1) Stochastic models need information at the molecular level as building blocks to construct the model properly and to validate simulation results obtained from the model. Experimental methods that yield molecular-level data have not been developed for biological systems, and 2) Stochastic simulations of a relatively small model, which contains less than 10 signaling components and their interactions, can pose large computational demands. However, application of the Gillespie method in small volume can reduce computation time to be comparable to that of deterministic simulation.
The Importance of Signaling Networks in Understanding Mechanisms that Underlie Disease and Drug Discovery
Cellular signaling networks are useful for drug discovery in three ways: 1) To develop an understanding of the biochemical mechanisms that underlie disease, which aids the discovery of novel drug targets, 2) To explain how current drugs affect the on-target (leading to therapeutic effect) and off-target (causing side effects and/or drug resistance) signaling pathways, which may lead to more informed prescribing methods and improved therapies, and 3) To lay out the interplay between signaling pathways in such a way that explains or facilitates the success of combination therapies. A dynamic relationship exists between the understanding of the biochemical mechanisms that underlie disease and drug discovery (Fig. 3). The compilation of data into a detailed, signaling network is central in properly choosing a drug target (109). Many network models are in place, such as those described for the EGFR and TLR networks in this review, which can be applied to drug discovery (110). Before pursuing a drug target, it is important to understand as thoroughly as possible the consequences of regulating the target of choice because of the sheer expense involved with drug development and clinical trials. This understanding may be gained by analyzing a computational model of the signaling network involved, generating a
knockout mouse, examining the chemical genetics of the target, and critically examining the current data on the drug target in the literature and databases (i.e., Chembank). Of the total number of proteins that have a function we currently understand, only a small fraction is drug targets. The pool of drug targets is evolving with the introduction of new drug discovery technologies, such as the cell signaling network analyses described in this review, combinatorial chemistry, chemical genetics, molecular informatics, and advanced high-throughput screening technologies. With a new direction in the medical eld toward personalized therapy regiments, it is increasingly important to expand the druggable network, and the enhanced global knowledge of signaling networks and the new drug discovery technology are indispensable in achieving this goal. Although signaling network analysis is essential to uncover new drug targets and aid in subsequently validating their potential, it also plays a role in studying roadblocks for approved/pipeline drugs, such as developed drug resistance or off-target effects. Network analysis combined with carefully designed proteomic experiments aid in the understanding of the mechanisms of resistance and in developing methods to overcome the resistance. For example, a study by Chen et al. (111) combined signaling network analysis and a carefully designed proteomic experiment to illuminate the signaling network involved with the resistance of ovarian cancer cells to cisplatin treatment. In the light of the abundant data on drug resistance in disease, many therapies are dosed in combinations to affect several pathways at once and/or gain a therapeutic advantage that stems from synergistic effects between drugs (112). An assembly of the data on the pathophysiology and biochemistry of cancer will allow treatment regimens to evolve toward targeting a network rather than a single protein (113). Efforts are currently underway to use a network analysis approach in understanding the effects of treatment with more than one drug (114). Alternatively, the combination of effects of two or more drugs can be used to uncover information about how the networks that each drug targets are connected (114). Combined with advances in high-throughput screening technologies, these approaches will be the powerhouse in the discovery of numerous novel therapeutic drug combinations and the most effective dosing schedules.
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O O
Discovery of components with potential for therapeutic intervention within cellular signaling network.
Validation of therapeutic potential of signaling components by chemical genetics or gene-knockout. Lead optimization and clinical trials.
O O O N O N H O O H2 N N H HN NH N O O Cl O
Identification of components in different pathways within signaling network that have potential for combination therapy.
150 125 100 75 50 25 0 0.6 0.9 1.2 1.5 1.8 2.1 2.4
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Figure 3 Intracellular signaling networks, disease, and drug discovery. A schematic is shown that represents the ways in which intracellular signaling networks play a role in the drug discovery and development process.
and identify drugs that can be used as therapeutic agents for diseases that arise from alterations in the regulatory capabilities of cell signaling networks.
Acknowledgment
This work was supported by National Institutes of Health Grants numbers GM54508, DK38761 and a contract from National Institute of Allergy and Infectious Diseases.
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See Also
Systems Biology Computational Chemistry in Biology Peptides Chemistry of Cyclic AMP in Signaling Cell Cycle, Computation and Modeling of Integrin Signaling Intercellular Signaling G-Protein Coupled Receptor (GPCR) Signaling Receptor Tyrosine Kinases Array-Based Techniques: Proteins Chemical Libraries: Screening for Biologically Active Small Molecules Synthetic Networks in Living Systems: Topics in Chemical Biology
Further Reading
Alon U. An Introduction to Systems Biology: Design Principles of Biological Circuits. 2006. Chapman & Hall/CRC Press, Boca Raton, FL. Helmreich E. Biochemistry of Cell Signaling, Oxford University Press, 2001. Maayan A, Blitzer RD, Iyengar R. Toward predictive models of mammalian cells. Annu. Rev. Biophys. Biomol. Struct. 2005; 34319 34349. Murray JD. Mathematical Biology: I. An Introduction. Springer, New York. 2002. Murray JD. Mathematical Biology: II. Spatial Models and Biomedical Applications. Springer, New York. 2003. Rangamani P, Iyengar R. Modelling spatio-temporal interactions within the cell. J. Biosci. 2007;32:157167.
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