Biochemistry of Signal Transduction and Regulation
Description
Thanks to its clear structure, hundreds of illustrative drawings, as well as chapter introductions and newly added study questions, this text excels as a companion for a course on biological signaling, and equally as an introductory reference to the field for students and researchers. Generations of students and junior researchers have relied on "the Krauss" to find their way through the bewildering complexity of biological signaling pathways.
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Content
Cell Signaling: Why, When and Where?
Intercellular Signaling
Hormones in Intercellular Signaling
Intracellular Signaling: Basics
Molecular Tools for Intracellular Signaling
PROPERTIES OF SIGNALING PROTEINS AND ORGANIZATION OF SIGNALING
Modular Structure of Signaling Proteins
Modular Signaling Complexes
Regulation of Signaling Enzymes by Effector Binding
Posttranslational Modifications in Cellular Signaling
Regulation by Phosphorylation
Protein Lysine Acetylation
Protein Methylation
Ubiquitin Modification of Proteins
Lipidation of Signaling Proteins
Scaffold Proteins
Organization of Signaling
THE REGULATION OF GENE EXPRESSION
The Basic Steps of Gene Expression
The Components of the Eukaryotic Transcription Machinery
The Principles of Transcription Regulation
The Control of Transcription Factors
Chromatin Structure and Transcription Regulation
RNA PROCESSING, TRANSLATIONAL REGULATION AND RNA INTERFERENCE
Pre-mRNA Processing
Regulation at the Level of Translation
Regulation by RNA Silencing
SIGNALING BY NUCLEAR RECEPTORS
Ligands of Nuclear Receptors
Principles of Signaling by Nuclear Receptors
Structure of Nuclear Receptors
Transcriptional Regulation by Nuclear Receptors
Regulation of Signaling by Nuclear Receptors
Subcellular Localization of Nuclear Receptors
Non-Genomic Functions of Nuclear Receptors and their Ligands
G PROTEIN-COUPLED SIGNAL TRANSMISSION PATHWAYS
Transmembrane Receptors: General Structure and Classification
Structural Principles of Transmembrane Receptors
G Protein-Coupled Receptors
Regulatory GTPases
The Heterotrimeric G-Proteins
Receptor-Independent Functions of Heterotrimeric G-Proteins
Effector Molecules of G-Proteins
GPCR Signaling via Arrestin
INTRACELLULAR MESSENGER SUBSTANCES: "SECOND MESSENGERS"
General Properties of Intracellular Messenger Substances
cAMP
cGMP and Guanylyl Cyclases
Metabolism of Inositol Phospholipids and Inositol Phosphates
Storage and Release of Ca2+
Functions of Phosphoinositides
Ca2+ as a Signal Molecule
Diacylglycerol as a Signal Molecule
Other Lipid Messengers
The NO Signaling Molecule
SER/THR-SPECIFIC PROTEIN KINASES AND PROTEIN PHOSPHATASES
Classification, Structure and Characteristics of Protein Kinases
Structure and Regulation of Protein Kinases
Protein Kinase A
The PI3 Kinase/Akt Pathway
Protein Kinase C
Ca2+/Calmodulin-Dependent Protein Kinases
Ser/Thr-specific Protein Phosphatases
SIGNAL TRANSMISSION VIA TRANSMEMBRANE RECEPTORS WITH TYRSINE-SPECIFIC PROTEIN KINASE ACTIVITY
Structure and Function of RTKs
Downstream Effector Proteins of RTKs
Nonreceptor Tyrosine-Specific Protein Kinases, Non-RTKs
Protein Tyrosine Phosphatases
Adaptor Molecules of Receptor Tyrosine Kinases
SIGNAL TRANSMISSIO VIA RAS PROTEINS
The Ras Superfamily of Monomeric GTPases
GTPase-Activating Proteins, GAPs, of the Monomeric GTPases
Guanine Nucleotide Exchange Factors, GEFs, of the Monomeric GTPases
Inhibitors of Guanine-Nucleotide Dissociation, GDIs
The Ras Family of Monomeric GTPases
Raf Kinase as an Effector of Signal Transduction by Ras Proteins
Further Ras Family Members: R-Ras, Ral and Rap
Reception and Transmission of Multiple Signals by Ras Protein
The Further Branches of the Ras Superfamily
INTRACELLULAR SIGNAL TRANSDUCTION: THE PROTEIN CASCADES OF THE MAP KINASE PATHWAYS
Organization and Components of MAPK Pathways
Regulation of MAPK Pathways by Protein Phosphatases and Inhibitory Proteins
Specificity in MAPK Activation and Organization in Multiprotein Complexes
The Major MAPK Pathways of Mammals
MEMBRANE RECEPTORS WITH ASSOCIATED TYROSINE KINASE ACTIVITY
Cytokines and Cytokine Receptors
The Jak-Stat Pathway
T and B Cell Receptors (TCRs and BCRs)
Signal Transduction via Integrins
OTHER TRANSMEMBRANE RECEPTOR CLASSES: SIGNALING BY TGFß-RECEPTORS, TNF-RECEPTORS, TOLL-RECEPTORS AND NOTH
TGFß Receptor and Smad Protein Singaling
Receptor Regulation by Intramembrane Proteolysis: The Notch Receptor
Tumor Necrosis Factor Receptor (TNFR) Superfamily
Toll-Like R
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Basics of Cell Signaling
1.1 Cell Signaling: Why, When, and Where?
One characteristic common to all organisms is the dynamic ability to coordinate constantly one's activities with environmental changes. The function of communicating with the environment is achieved through a number of pathways that receive and process signals originating from the external environment, from other cells within the organism, and also from different regions within the cell.
In addition to adopting the function of an organism to environmental changes in a signal-directed way, other essential features of multicellular organisms also require the coordinated control of cellular functions.
The formation and maintenance of the specialized tissues of multicellular organisms depend on the coordinated regulation of cell number, cell morphology, cell location, and the expression of differentiated functions. Such coordination results from a complex network of communication between cells in which signals produced affect target cells where they are transduced into intracellular biochemical reactions that dictate the physiological function of the target cell (Figure 1.1). The basis for the coordination of the physiological functions within a multicellular organism is intercellular signaling (or intercellular communication), which allows a single cell to influence the behavior of other cells in a specific manner. As compared to single-cell organisms, where all cells behave similarly within a broad frame, multicellular organisms contain specialized cells forming distinct tissues and organs with specific functions. Therefore, the higher organisms have to coordinate a large number of physiological activities such as:
- Intermediary metabolism
- Response to external signals
- Cell growth
- Cell division activity
- Differentiation and development: coordination of expression programs
- Cell motility
- Cell morphology.
Intercellular signaling:
- Communication between cells.
Intracellular signaling:
- Signaling chains within the cell, responding to extracellular and intracellular stimuli.
Figure 1.1 Intercellular and intracellular signaling. The major method of intercellular communication employs messenger substances (hormones) that are secreted by signal-producing cells and registered by target cells. All cells produce and receive multiple, diverse signals. The extracellular signals are transduced into intracellular signaling chains that control many of the biochemical activities of a cell and can also trigger the formation of further extracellular signals.
Signals generated during intercellular communication must be received and processed in the target cells to trigger the many intracellular biochemical reactions that underlie the various physiological functions of an organism. Typically, a large number of steps is involved in the processing of the signal within the cell, which is broadly described as intracellular signaling. Signal transduction within the target cell must be coordinated, fine-tuned and channeled within a network of intracellular signaling paths that finally trigger distinct biochemical reactions and thus determine the specific functions of a cell. Importantly, both intercellular and intracellular signaling are subjected to regulatory mechanism that allow the coordination of cellular functions in a developmental and tissue-specific manner.
1.2 Intercellular Signaling
Intercellular signal transduction influences nearly every physiological reaction. It ensures that all cells of a particular type receive and transform a signal. In this manner, cells of the same type react synchronously to a signal. A further function of intercellular communication is the coordination of metabolite fluxes between cells of various tissues.
In higher organisms, intercellular signaling pathways have the important task of coordinating and regulating cell division. The pathways ensure that cells divide synchronously and, if necessary, arrest cell division and enter a resting state.
Intercellular signaling:
- Processes sensory information
- Controls
- Metabolic fluxes
- Cell division
- Growth
- Differentiation
- Development.
Cellular communication assumes great importance in the differentiation and development of an organism. The development of an organism is based on genetic programs that always utilize inter- and intracellular signaling pathways. Signal molecules produced by one cell influence and change the function and morphology of other cells in the organism.
Intercellular signaling pathways are also critical for the processing of sensory information. External stimuli, such as optical and acoustic signals, stress, gradients of nutrients, and so on, are registered in sensory cells and are transmitted to other cells of the organism via intercellular signaling pathways.
1.2.1 Tools for Intercellular Signaling
Various forms of communication between cells are currently known (Figure 1.2):
- Extracellular messengers: Cells send out signals in the form of specific messenger molecules that the target cell transmits into a biochemical reaction. Signaling cells can simultaneously influence many cells by messenger molecules so as to enable a temporally coordinated reaction in an organism.
- Gap junctions: Communication between bordering cells is possible via direct contact in the form of “gap junctions.” Gap junctions are channels that connect two neighboring cells to allow a direct exchange of metabolites and signaling molecules between the cells.
- Cell–cell interaction via cell-surface proteins: Another form of direct communication between cells occurs with the help of surface proteins. In this process, a cell-surface protein of one cell binds a specific complementary protein on another cell. As a consequence of the complex formation, an intracellular signal chain is activated which initiates specific biochemical reactions in the participating cells. Communication is then only possible upon direct contact between the target cell and the surface protein of the partner cell.
- Electrical signaling: A further intercellular communication mechanism relies on electrical processes. The conduction of electrical impulses by nerve cells is based on changes in the membrane potential. The nerve cell uses these changes to communicate with other cells at specialized nerve endings, the synapses. It is central to this type of intercellular communication that electrical signals can be transformed into chemical signals. This type of communication will not be discussed in this book.
Cells communicate via:
- Messenger substances
- Gap junctions
- Surface proteins
- Electrical signals.
Figure 1.2 The principal mechanisms of intercellular communication. (a) Communication via intercellular messengers; (b) Communication via gap junctions, which provide direct connections between cells. Gap junctions are coated by proteins (shown as circles in the figure) that can have a regulatory influence on the transport; (c) Communication via surface proteins.
In the following, the main emphasis will be on the intercellular communication via extracellular messengers, the hormones.
1.2.2 Steps of Intercellular Signaling
In the communication between cells of an organism, the signals (messengers such as hormones) are produced in specialized cells. The signal-producing function of these cells is itself regulated, so that the signal is only produced upon a particular stimulus. In this way, signaling pathways can be coupled to one another and coordinated.
The following steps are involved in intercellular communication (Figure 1.3).
Figure 1.3 The individual steps of intercellular communication. On receipt of a triggering stimulus, the signal is transformed into a chemical messenger within the signaling cell. The messenger is secreted and transported to the target cell, where the signal is registered, transmitted further, and finally converted into a biochemical reaction. Processes of termination or the regulation of communication, which can act at any of the above steps, are not shown.
1.2.2.1 Formation of a Signal in the Signal-Producing Cell as a Result of an External Trigger
Most extracellular messengers are produced in response to external triggers and are released by exocytosis. Physical stimuli such as electrical signals, changes in ion concentration or, most frequently, other extracellular signaling molecules, serve as a trigger to increase the amount of the messenger available for extracellular communication. The mechanisms by which the external trigger signals increase the amount of extracellular messenger are diverse, and include stimulation of the biosynthesis of the messenger, an increased production of the mature messenger from precursors, and the release of the messenger from a stored form. The latter mechanism is used extensively in the release of hormones of the neural system (neurotransmitters) in response to electrical signals for example, at synapses.
Steps of intercellular signaling:
- Trigger signal induces release of stored messenger or stimulates its biosynthesis
- Transport to target cell
- Receipt of signal by the target...
