Beruflich Dokumente
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Jason M. Haugh,
North Carolina State University, Raleigh, North Carolina
doi: 10.1002/9780470048672.wecb646
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Signal Transduction Networks: Biologic Background Signal Transduction Models: Chemical/Physical Foundations Mathematical Modeling Tools and Techniques Applications of Mathematical Modeling in Cell Signaling Prospects and Challenges
Intracellular signaling networks, which are composed of interconnected biochemical pathways, regulate and actuate responses such as cell-cycle progression and cell migration, survival, and differentiation. Although our knowledge of the intricate biochemical mechanisms at the level of individual proteins and molecular interactions is ever expanding, those details leave us with an even murkier view of how the complex network operates as a whole. True understanding requires knowing not only what happens at the molecular level but also how these mechanisms inuence the precise magnitude, timing, and spatial localization of signal transduction processes. Hence, mathematical modeling and analysis has emerged in recent years as a legitimate approach for interpreting experimental results and generating novel hypotheses for additional study and model renement. Once conducted in isolation and scorned by most biologists, quantitative modeling has moved into the mainstream as a powerful tool for the analysis of cell signaling. In this article, the biological, chemical, and physical underpinnings of this approach are presented, as are its current applications and future challenges.
Biological research has been focused increasingly on the basis for cell regulation and function at the molecular level, and as a result, we now have a detailed map of how intracellular molecules are organized to form signal transduction pathways and cascades (Fig. 1). The protein jungle, as articulated by Bray a decade ago (1), is characterized by a wealth of qualitative information about the connectivity of pathways (the so-called interactome) but relatively little in the way of quantitative measurements. For example, one might wish to know how some meaningful quantity, such as the activity of a particular enzyme, changes as a function of time and stimulus in a given cell type. A quantitative assay could be developed for measuring that quantity. Understanding those kinetics fully, however, would require detailed knowledge of the underlying regulation mechanisms, of which several typically exist. Reconstituting those mechanisms in a test tube, in most cases, is prohibitively difcult, as is their systematic manipulation in the cell. Ultimately, the regulatory mechanisms would have to be characterized in terms of equilibrium and rate constants and intracellular concentrations. Finally, it would be useful to develop a correlation between the magnitude and timing of that pathway and the quality of cellular responses, such as rates of proliferation and probability of survival. Even if obtaining such a data set were feasible, it is not
obvious how one would analyze it and extract useful insights and predictions from it. This article deals with the mathematical modeling of signal transduction pathways and networks, which has emerged as a powerful tool that can aid in interpreting such quantitative data sets. In principle, quantitative models offer three advantages over the conceptual arrow diagrams that are encountered routinely in the signaling literature. First, a consequence of their mathematical construction is that they are precise, and the inherent assumptions may be laid out clearly. Second, to the extent that the underlying molecular biology is known, quantitative models can be mechanistic . Mechanistic models are based on established physico-chemical principles, in which case the form of the model equations is determined to a signicant extent by the hypothetical mechanisms assumed. Thus, it is possible to evaluate the relative merits of different candidate mechanisms by comparison with experiment. In contrast with mechanistic models, phenomenological models are meant only to capture experimentally observed relationships in an empirical way. They naturally are less powerful, but they serve a denite and useful role and are appropriate in situations in which the underlying mechanisms are less certain. A prominent example is the sort of statistical, correlative models central to the eld of bioinformatics; although such approaches 1
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STIMULUS Receptor Grb2 Sos Shc RasGAP Shp2 PIP3 Akt Rac/Pak Gab/IRS PI3K PIP2 PKC Ca2+ Downstream substrates PLC DAG + IP3 Src-family kinases
Figure 1 Partial representation of a signal transduction network, mediated by a cell surface receptor. The molecules are organized hierarchically (roughly, from top to bottom) according to their functions as adaptors, receptor-recruited enzymes, membrane-associated substrates, and effector kinases. Arrows represent activation mechanisms, whether by complex formation or covalent modication; T bars indicate negative regulation.
are not discussed in detail here, they have been applied with great success in the analysis of signal transduction networks (2, 3). Third, a model that has been validated against an appropriate amount of quantitative data may be used to design and predict the outcomes of novel experiments and generate new hypotheses. Evaluating those outcomes by experiment inevitably reveals inconsistencies in the model, and hence the model must be rened in an iterative manner. This is in essence the same process by which qualitative, conceptual models are rened over time, although one could argue that quantitative models are far more sensitive to hypothesis testing because of their precise nature.
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sequences (Src homology 3 domains); other domains are responsible for interactions with lipids (pleckstrin homology, FYVE, C1, and C2 domains). Together, these domains mediate the formation of multimolecular complexes that regulate the activities and mediate the targeting of signaling enzymes. Many signaling enzymes have a handful of such domains, whereas other signaling proteins called adaptors have no enzymatic function but possess domains that mediate the binding of enzymes to signaling complexes. From the standpoint of modeling, this complexity presents a denite challenge.
and endoplasmic reticulum, have been found more recently to serve as platforms for certain signaling interactions (15).
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(a)
(b)
Figure 2 Mathematical modeling of cellular processes: an illustrative example. A. Consider the following mechanism for ligand/receptor dynamics: Cell surface receptors (R) are synthesized at a constant rate and bind reversibly with a ligand (L) to form a complex (C). Both free and bound receptors are internalized and later degraded, but they do so at different rates. Based on this mechanism, the law of mass action is used to construct the conservation equations for R and C. B. Addition of transport effects. In the case of autocrine signaling, the cell is both the source of the secreted ligand and the responder. Spherical geometry is adopted, and a simple reaction/diffusion model is used to calculate the ligand concentration prole at steady state, assuming a dilute suspension of cells and the same receptor dynamics as in A. This prole is given by [L] = [L]s (a / r ), where [L]s is the value of [L] at the cell surface (r = a). It is shown readily that the maximum value of [L]s , achieved when no receptor binding exists, is equal to aVL / DL , where VL is the cell rate of ligand secretion per unit area and DL is the diffusion coefcient of the ligand. The actual value of [L]s relative to the maximum is found to be a function of only two dimensionless variables: the ratio of receptor and ligand synthesis rates (equal to 1 for the plotted results) and a parameter that characterizes the efciency of the receptor-mediated ligand capture (dened as (akf R0 / DL )[ke / (kr + ke )], where R0 = VR / kt ; values of 100, 10, 1, and 0.1 were used here).
solved in conjunction with appropriate boundary conditions that together specify the problem (Fig. 2b). For a species in solution present at a concentration Ci (x , t ), where x is a spatial position vector (coordinates in x , y , z ) and t is time, the conservation equation is represented precisely as follows: Ci = Ni + t vij rj
j
Here, N i is a vector that species the outward ux of species i ; thus, taking its gradient ( / x ) and adding a minus sign gives the net rate of species i into location x by mass transport. The second term accounts for the net generation of species i by reactions j , dened by the aforementioned rate laws rj and stoichiometry coefcients ij . Concentrations of species associated with membranes usually are expressed on a per unit surface area basis, and a planar geometry generally is adopted for the membrane. For molecules in solution, the ux Ni is the sum of two contributions: a convection term that accounts for the bulk ow 4
of the uid, given by vCi (v is the uid velocity vector), and a diffusive ux term Ji that accounts for the tendency of molecules to disperse in solution. In the cellular context, it is important to note that the convective term also might include consideration of active transport processes, such as those actuated by motor proteins. To proceed, a semi-empirical constitutive equation that relates the form of Ji to macroscopic variables must be invoked. The only suitable theory that has been offered in that regard is attributed to Fick, who in 1855 asserted that the net diffusive ux of species i is proportional to its gradient in mole fraction; Einsteins theory of Brownian motion, published 50 years later, is the microscopic analog of Ficks Law. If species i is present in a dilute solution, Ficks Law reduces to Ji = Di Ci The diffusion coefcient Di characterizes the mobility of species i in solution, determined by the thermal energy that promotes translational motion and the viscous drag force that opposes that motion. Substituting the expression above into the conservation
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equation and assuming that diffusion dominates over convection and Di is constant, one obtains the common reactiondiffusion equation: Ci vij rj = Di 2 C i + t
j
where 2 is the Laplacian operator (sometimes written as ). Despite its lack of grounding in pure physical chemistry, which has been a source of some contention (16), Ficks Law and the reactiondiffusion equation have been used with great success to characterize processes in the cell cytoplasm and at cell membranes. Given the empirical nature of Ficks Law and the notable differences between molecular motions at microscopic (nm) versus macroscopic (m) length scales, it is more appropriate to refer to Di as the apparent diffusivity or macroscopic mobility coefcient when applied to cell-associated molecules. An alternative approach, from the standpoint of modeling, is to develop a microscopic description of the system using Monte Carlo-based simulations (see the section Mathematical Modeling Tools and Techniques below).
they evolve in a deterministic fashion, according to the aforementioned conservation equations and their initial and boundary constraints. The implementation of such models involves the solution of ordinary and partial differential equations (ODEs and PDEs, respectively). ODEs commonly are encountered in kinetic models of cell signaling systems in which the species concentrations are assumed to be spatially homogeneous within the cell/cell compartment or are averaged over the domain in an appropriate way. In kinetic models of even modest complexity, the ODEs are nonlinear and therefore must be solved using numerical methods. With the advent of efcient, implicit solution algorithms and steadily increasing computing power, handling even large systems of ODEs is straightforward and the integration of these algorithms in various software packages is widespread. Solution of PDEs, commonly encountered in spatial modeling, is more complicated and computationally intensive by comparison, but several approximate numerical methods are available for this purpose. These include the nite difference , nite volume , and nite element methods, which vary according to their ease of implementation and applicability. The nite element method is the most complicated but generally applicable method for complex domain geometries; numerous software packages that implement this method are available, although the most powerful commercial packages are quite expensive. The freely available and user-friendly virtual cell software environment, which uses the nite volume method, has been used extensively for spatial modeling of intracellular processes (19). Several challenges are encountered in spatial modeling, regardless of the method used. First, the method and the accuracy of its computed results need to be validated. This requirement typically is achieved by testing the method on a simpler problem that has an analytical solution for comparison and by conrming that changes in the mesh size and time step do not affect the results signicantly. Second, the amount of computation needed rises dramatically as the geometric complexity of the model increases from one up to three spatial coordinates, and a temptation exists to oversimplify the domain geometry to reduce the dimensionality of the problem. Finally, certain cell biological processes, such as cell motility, demand advanced modeling features such as the coupling of cell mechanics and chemical kinetics and the handling of moving boundaries, which can make the problem computationally prohibitive without the introduction of simplifying assumptions.
Continuum models
The most common approach in mechanism-based modeling is to model the system as a continuum. The underlying assumption is that the state variables of the system (e.g., species concentrations) vary continuously in time and space and that, therefore,
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to probabilities of the various rate processes. This method is easy to implement and exact, but it is computationally inefcient for so-called stiff problems that possess a broad range of characteristic time scales. Approximate adaptations of the technique, using a method called tau leaping , allows more efcient computation of stiff systems albeit with a potential loss in accuracy (24, 25). Another approximate approach, valid in the limit of large numbers of molecules, is the stochastic differential equation method, which also is referred to as the chemical master equation or chemical Langevin equation approach. In this method, the probabilities of the various states being populated by different numbers of molecules evolve in time according to ODEs. Although this method is not necessarily more efcient or applicable to stiff systems, it serves as the starting point for several powerful approximations that are valid in certain limiting cases (20). Methods for modeling spatially uctuating reactiondiffusion systems, wherein molecules are treated as discrete particles whose coordinates are tracked and moved with time, also are available. These methods account for stochastic transitions as motivated above and are appropriate when concentration gradients are expected, as in the case of diffusion-controlled reactions. They also allow one to generate movies of the simulations to visualize the constituent processes in action. In the lattice Monte Carlo method, particles occupy nodes on a regularly spaced grid and move to adjacent nodes according to probabilities determined by the diffusion coefcient (and by long-range intermolecular potentials, if applicable). Changes in state occur probabilistically, and intermolecular interactions are subject to specic rules. For example, when the molecules are treated as point particles, interactions might occur in the next time step if the two species occupy adjacent nodes. In this limit, the method is very efcient computationally but suffers in accuracy because of its inability to resolve off-lattice events, which is especially signicant when concentration gradients are steep. The Brownian dynamics or dissipative particle dynamics method is similar to the lattice Monte Carlo except that the particles adopt coordinates that are continuous throughout the domain. Thus, this method is accurate but also more computationally intensive. Both methods have been used in the context of signal transduction, particularly to study processes at cell membranes (26, 27).
or thousands, is generated automatically in the form of a system of ODEs; alternatively, the rules can be used in a stochastic simulation wherein the species of the network are formed spontaneously. Efforts are underway to extend this approach to the spatial domain as well.
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Figure 3 The MAPK cascade. A signaling cascade generally refers to a series of enzyme modication processes, as in the activation of extracellular signal-regulated kinase (Erk) isoforms, which are mammalian mitogen-activated protein kinases (MAPKs). The rst kinase, Raf, is activated (indicated by an asterisk) by numerous inputs, allowing it to phosphorylate MEK on two sites; Erk is phosphorylated dually in a similar fashion by MEK. Each phosphorylation event is thought to require a separate encounter between enzyme and substrate, which gives rise to interesting dynamical properties. Not depicted here, but equally important, are the phosphatases that catalyze the reverse reactions.
imaging Ca2+ in living cells, both kinetic and spatial models of calcium dynamics have been explored in ne detail. Analyzed most extensively have been the mechanisms that give rise to a single calcium spike or sustained Ca2+ oscillations (4044) and the propagation of calcium waves (4549). These and other calcium models have proved useful in the elds of neuroscience, immunology, and cardiac biology. Other receptor-proximal signal transduction interactions and pathways to which mathematical modeling and/or analysis have been applied successfully include the phosphoinositide 3-kinase pathway (5054), which is central for signaling numerous responses including directed cell migration (chemotaxis), survival, and proliferation; the phospholipase C pathway/inositol cycle (44, 55, 56), which is important for intracellular calcium release and cell migration; and the actions and regulation of nonreceptor tyrosine kinases and protein phosphatases (5760). Further downstream, models describing the regulation of transcription factors, most notably NFB (61) and the STATs (signal transducing activators of transcription) (62), have been offered.
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Further Reading
Kholodenko BN. Cell-signalling dynamics in time and space. Nat. Rev. Mol. Cell. Biol. 2006;7:165176. Lauffenburger DA, Linderman JJ. Receptors: Models for Binding, Trafcking, and Signaling. 1993. Oxford University Press, New York. Maayan A, Blitzer R.D., Iyengar R. Toward predictive models of mammalian cells. Annu. Rev. Biophys. Biomol. Struct. 2005;34:319349. Mogilner A, Wollman R, Marshall WF. Quantitative modeling in cell biology: what is it good for? Dev. Cell 2006;11:279287. Slepchenko BM, Schaff JC, Carson JH, Loew LM. Computational cell biology: spatiotemporal simulation of cellular events. Annu. Rev. Biophys. Biomol. Struct. 2002;31:423441. Tyson JJ, Chen KC, Novak B. Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Curr. Opin. Cell Biol. 2003;15:221231.
See Also
Cell Cycle, Computation and Modeling of Chemotaxis Receptor-Ligand Interactions Signal Cascades, Protein Interaction Networks in Systems Biology
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