Systems Biology of Cell Signaling

Recurring Themes and Quantitative Models

James Ferrell

• Publisher: Garland Science
• Year: 2021
• Print ISBN: 9780367643836
• eBook ISBN: 9781000430783
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

How can we understand the complexity of genes, RNAs, and proteins and the associated regulatory networks? One approach is to look for recurring types of dynamical behavior. Mathematical models prove to be useful, especially models coming from theories of biochemical reactions such as ordinary differential equation models. Clever, careful experiments test these models and their basis in specific theories. This textbook aims to provide advanced students with the tools and insights needed to carry out studies of signal transduction drawing on modeling, theory, and experimentation. Early chapters summarize the basic building blocks of signaling systems: binding/dissociation, synthesis/destruction, and activation/inactivation. Subsequent chapters introduce various basic circuit devices: amplifiers, stabilizers, pulse generators, switches, stochastic spike generators, and oscillators. All chapters consistently use approaches and concepts from chemical kinetics and nonlinear dynamics, including rate-balance analysis, phase plane analysis, nullclines, linear stability analysis, stable nodes, saddles, unstable nodes, stable and unstable spirals, and bifurcations. This textbook seeks to provide quantitatively inclined biologists and biologically inclined physicists with the tools and insights needed to apply modeling and theory to interesting biological processes.

Key Features:

• Full-color illustration program with diagrams to help illuminate the concepts
• Enables the reader to apply modeling and theory to the biological processes
• Further Reading for each chapter
• High-quality figures available for instructors to download

1

INTRODUCTION

IN THIS CHAPTER . . .

1. 1.1 SIGNAL TRANSDUCERS ARE CELLULAR COMPONENTS THAT ACT MAINLY BY REGULATING OTHER CELLULAR COMPONENTS
2. 1.2 THE SIGNAL TRANSDUCTION PARTS LIST IS LONG
3. 1.3 SIGNAL TRANSDUCTION IN BACTERIA IS ACCOMPLISHED BY SHORT, (MOSTLY) LINEAR, (MOSTLY) NON-INTERCONNECTED PATHWAYS
4. 1.4 THE EGFR SYSTEM IS DEEP, INTERCONNECTED, AND COMPLICATED
5. 1.5 COMPLICATED SYSTEMS CAN BE SIMPLIFIED BY ASSUMING MODULARITY
6. 1.6 ORDINARY DIFFERENTIAL EQUATIONS PROVIDE A POWERFUL FRAMEWORK FOR UNDERSTANDING MANY SIGNALING PROCESSES
7. 1.7 THEORY CAN HELP HIGHLIGHT THE COMMONALITIES OF DIVERSE BIOLOGICAL PHENOMENA
8. 1.8 SIX BASIC TYPES OF RESPONSE ARE SEEN OVER AND OVER AGAIN IN CELL SIGNALING
9. 1.9 FIVE OR SIX BASIC CIRCUIT MOTIFS ARE SEEN OVER AND OVER AGAIN IN SIGNALING SYSTEMS
10. SUMMARY
11. MOVING FORWARD
12. FURTHER READING

DOI: 10.1201/9781003124269-1

SIGNAL TRANSDUCTION COMPONENTS AND SYSTEMS

All living cells continually detect and respond to external signals. This is true for prokaryotes, whether they are living alone or in biofilms, and it is even more manifestly true in multicellular eukaryotes, where communication between cells and coordination of the cells’ behavior enables the organism to function as a unified whole. In large multicellular organisms like us humans, cells receive signals from their immediate neighbors through short-range signals like neurotransmitters and cell-surface molecules. They receive signals from more distant neighbors via longer range diffusible molecules such as morphogens and from still-more distant neighbors by means of hormones that flow through the circulatory system. They receive signals from the outside world via sense organs. Cells also monitor their own internal status, and there is a great deal of overlap between the cellular components involved in cell–cell communication and internal monitoring. Ultimately a cell processes input signals through a process termed signal transduction, shown schematically in Figure 1.1.

FIGURE 1.1 A schematic view of a generic signal transduction process.

Signal transduction allows us to see, hear, taste, smell, and feel. It allows us to think, remember, and move. Signaling determines if and when a cell grows and divides and often determines if and when it dies. Signaling drives differentiation, enables the formation of all of our tissues and organs during development, and maintains them after they have formed. It allows our blood to clot and our immune system to fight infection. Signaling allows us to heal our wounds and to adapt to the unpredictable world around us. Signaling proteins are the targets of six of the ten most widely prescribed drugs in the United States (TABLE 1.1) and are the targets of probably all recreational drugs.

TABLE 1.1 Most Widely Prescribed Drugs in the United States

				U.S. Prescriptions (millions)
	Drug	Indications	Mechanism of Action	2014	2015	2016	2017	2018
1	Atorvastatin	High cholesterol	Inhibits cholesterol synthesis	74	94	97	105	112
2	Levothyroxine	Hypothyroidism	Activates thyroid hormone receptors	100	113	114	102	105
3	Lisinopril	Hypertension	Inhibits the last step in the production of the hormone angiotensin II	114	110	109	104	97
4	Metformin	Type II diabetes mellitus	Inhibits mitochondrial respiratory-chain complex 1	85	83	80	78	84
5	Amlodipine	Hypertension, angina pectoris	Inhibits voltage-gated calcium channels	63	71	75	73	76
6	Metoprolol	Hypertension, angina pectoris, and myocardial infarction	Inhibits β1-adrenergic receptors	71	69	73	67	71
7	Albuterol	Asthma and chronic obstructive pulmonary disease	Activates β2-adrenergic receptors	48	50	47	50	61
8	Omeprazole	Gastroesophageal reflux disease and gastric ulcers	Inhibits H^+/K^+ ATPase	71	71	70	58	58
9	Losartan	Hypertension	Inhibits angiotensin II receptors	37	47	49	52	51
10	Simvastatin	High cholesterol	Inhibits cholesterol synthesis	97	89	80	73	66

Six of the ten drugs on this list work by activating or inhibiting signaling proteins, or by inhibiting the production of a hormone. These are highlighted in italic. Source: Agency for Healthcare Research and Quality. Total purchases in by prescribed drug, United States, 1996–2018. Medical Expenditure Panel Survey. Generated interactively: Wed Jan 20 2021.

Thus, signal transduction is of special importance to neurobiologists, cell biologists, developmental biologists, hematologists, immunologists, and pharmacologists. Increasingly, it has been attracting the attention of physicists, control theorists, and electrical engineers—scientists who want to use the tools of their fields to deepen our understanding of this fascinating but highly complicated aspect of life.

SIGNAL TRANSDUCTION IS CARRIED OUT BY SYSTEMS OF VARYING COMPLEXITY

1.1 SIGNAL TRANSDUCERS ARE CELLULAR COMPONENTS THAT ACT MAINLY BY REGULATING OTHER CELLULAR COMPONENTS

Deciding which components of a cell count as signal transducers, and which do not, is not a trivial task. Often signal transducers are proteins or protein complexes, but they can also be RNAs, small molecules, or ions. Perhaps a few examples will help us sharpen our ideas of what is and what is not a signal transducer.

Receptors, protein kinases, and small G-proteins are signaling proteins, but glycolytic enzymes and motor proteins are not. MicroRNAs are signal transducers—they regulate mRNA stability and translation—but mRNAs, tRNAs, and rRNAs are not. Calcium ions are signal transducers—they regulate protein kinases, phosphoprotein phosphatases, motor proteins, and many other proteins—but magnesium ions are not. The membrane lipids PIP₃ and diacylglycerol are signal transducers—they both regulate particular protein kinases—but phosphatidylcholine is not; it (mainly) acts as a structural component of membranes. And the nucleotide cAMP is a signal transducer, allosterically regulating a subunit of protein kinase A, but its relative ADP is not; it is a metabolic intermediate. In general, signal transducers are cell components that vary dynamically in abundance or activity and affect a cell’s function by regulating something else; they are more like managers than workers.

Some consider transcription factors—DNA-binding proteins that regulate the transcription of specific genes—to be terminal effectors of signal transduction systems rather than being signal transducers themselves. Here the main distinction is time scales; transcription is often slower than signal transduction processes like ion fluxes or protein phosphorylation. In other respects, though, transcription factors are just like other signal transduction proteins, relaying signals from upstream inputs (often protein kinases) to downstream targets (the genes whose transcription they regulate).

1.2 THE SIGNAL TRANSDUCTION PARTS LIST IS LONG

We now have a close-to-comprehensive parts list for the signaling proteins and other signaling molecules from all of the widely studied model organisms (e.g., humans, mice, Drosophila melanogaster, Caenorhabditis elegans, Saccharomyces cerevisiae, and Escherichia coli). The simplest of these model organisms in terms of the length of the parts list is, by a wide margin, the prokaryote E. coli. Many of its signaling pathways make use of one of 29 histidine-specific protein kinases, and these kinases phosphorylate about an equal number of downstream substrate proteins. Compared to the numbers of protein kinases and kinase substrates involved in mammalian signaling, these numbers are small, but still, these are the two largest families of paralogous genes in E. coli. In any case, with this limited cast of components, it is possible for a diligent student of cell signaling to acquire a reasonably co...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Detailed Contents
• Preface
• Acknowledgements
• Author
• Chapter 1: Introduction
• Chapter 2: Receptors 1: Monomeric Receptors and Ligands
• Chapter 3: Receptors 2: Multimeric Receptors and Cooperativity
• Chapter 4: Downstream Signaling 1: Stoichiometric Regulation
• Chapter 5: Downstream Signaling 2: Covalent Modification
• Chapter 6: Downstream Signaling 3: Regulated Production or Destruction
• Chapter 7: Cascades and Amplification
• Chapter 8: Bistability 1: Systems with One Time-Dependent Variable
• Chapter 9: Bistability 2: Systems with Two Time-Dependent Variables
• Chapter 10: Transcritical Bifurcations in Phase Separation and Infectious Disease
• Chapter 11: Negative Feedback 1: Stability and Speed
• Chapter 12: Negative Feedback 2: Adaptation
• Chapter 13: Adaptation 2: Incoherent Feedforward Regulation and State-Dependent Inactivation
• Chapter 14: Negative Feedback 3: Oscillations
• Chapter 15: Relaxation Oscillators
• Chapter 16: Excitability
• Chapter 17: Wrap-Up
• Glossary
• Index