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3.9 Summary
Heterotrimeric G proteins are tethered to the internal surface of the plasma membrane, and are activated by conformational change within 7TM receptors. There are many different α subunits (and a few βγ...
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3.8 Activation of transcription factors
We have already come across several examples of signalling pathways leading to activation (or inactivation) of transcription factors, which in turn modulate transcription of sets of genes leading to,...
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3.7 Protein phosphatases
Together with inositolphospholipid phosphatases, protein phosphatases are key regulators of signal transduction pathways. Like protein kinases, protein phosphatases are either tyrosine phosphatases...
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3.6.2 The JAK–STAT pathway
Another important protein kinase pathway is the JAK–STAT pathway. Cytokines (Section 2.2), are frequently used for signalling between cells of the immune system. Cytokine-induced signal transduction...
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3.6.1 The MAP kinase pathway
The MAP kinase pathway is so called because the last component of the pathway was originally identified as a kinase activity in EGF-stimulated cells – hence the name ‘mitogen-activated protein kinase’...
View Article3.6 Protein kinases
Protein kinases phosphorylate proteins either at tyrosine residues (tyrosine kinases), or at serine and threonine residues (serine–threonine kinases), or on any of these three amino acids...
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3.5 Monomeric G proteins
We shall discuss monomeric G proteins (also called small G proteins or small GTPases) separately from the trimeric G proteins for three reasons: their upstream activators are different, they tend to...
View Article3.4.3 Cyclic GMP
Cyclic GMP (cGMP) is a second messenger with many similarities to cAMP. It is synthesized from GTP by guanylyl cyclase, and degraded to 5´- GMP by cyclic GMP phosphodiesterases. Some of the targets of...
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3.4.2 Cyclic AMP
The concentration of cyclic AMP (cAMP) in the cytosol increases 20-fold within seconds of an appropriate stimulus. This is achieved by the action of the plasma membrane-embedded protein adenylyl...
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3.4.1 Calcium ions
The Ca2+ concentration is normally low in the cytosol (~10–7 mol 1–1) compared with the extracellular space (~10–3 mol 1−1). There are several mechanisms for achieving this. The most widespread are...
View Article3.4 Second messengers
In the previous section, we have discussed the principles of second messengers (Section 1.5) and, in particular, those produced by PLC (IP3 and DAG) and PI3 kinase (PI(3,4)P2 and PI(3,4,5)P3). We shall...
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3.3.2 Phospholipase C (PLC)
Members of this family of enzymes contain two catalytic domains and several protein binding domains (Figure 13). The PH domain can temporarily tether phospholipase C to the membrane by attachment...
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3.3.1 Phosphatidylinositol 3-kinase (PI 3-kinase)
Members of this family of lipid kinases usually have two subunits: one is a catalytic subunit with a lipid kinase domain and the other is a regulatory subunit, which contains two SH2 domains and a SH3...
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3.3 Lipid-modifying enzymes
The internal surface of the plasma membrane provides a useful environment for spreading signals received by surface receptors around the cell. Several specialist enzymes are activated by membrane-bound...
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3.2 Trimeric G proteins
G proteins are attached to the cytosolic face of the plasma membrane, where they serve as relay proteins between the receptors and their target signalling proteins.Trimeric G proteins interact with 7TM...
View Article3.1 Introduction
We are now ready to describe in detail the major intracellular signalling pathways responsible for relaying the signal from the surface receptor to evoke a cellular response. This section will deal...
View Article2.6 Summary
Receptors comprise a limited number of structural motifs, which determine binding affinity and specificity of receptor–ligand complexes. Some ligands bind to several receptors and some receptors bind...
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2.5 Intracellular receptors
Signal receptors are usually located at the cell surface. However, it is important to remember that there are some groups of receptors that do not fit into the general signal transduction model set out...
View Article2.4 Receptor inactivation
As with all signalling components, receptors need to be switched off as well as on. Receptor inactivation can operate in several ways including removal of the ligand by degradation or sequestration,...
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2.3.4 Recruiter receptors
Enzyme-associated or recruiter receptors also form dimers (or oligomers) on activation by their ligand, in a similar way to receptors with intrinsic enzymatic activity. Dimerization facilitates an...
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2.3.3 Receptors with intrinsic enzymatic activity
Receptors with intrinsic enzymatic activity are the second biggest group of receptors after the GPCRs. They include four types according to the form of enzymatic activity of the intracellular domain...
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2.3.2 Seven-helix transmembrane (7TM) receptors
Although in unicellular organisms such as the yeast S. cerevisiae there are only two classes of 7TM receptors, the pheromone and glucose receptors, multicellular organisms have many more, accounting...
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2.3.1 Ion-channel receptors
Nicotinic cholinergic receptors are probably the best studied of all receptors, firstly because they are present throughout skeletal muscle, and secondly because there are plenty of natural and...
View Article2.3 Receptor activation
Receptors may be activated by conformational change (for example, ion-channel receptors such as nicotinic receptors, and 7TM receptors such as muscarinic receptors and adrenergic receptors), by...
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2.2 Receptor specificity
Binding of an extracellular signal to its receptor involves the same type of interactions as those between an enzyme and its substrate. Receptor specificity depends on the binding affinity between the...
View Article2.1 Introduction
Every receptor has to be able to recognize its particular ligand in a specific manner, and become activated by it in such a way that it transmits the signal to the cell. We shall deal with receptor...
View Article1.9 Summary
In a basic model of signal transduction, a signalling molecule binds to a specific receptor, and this activates a sequence (or web) of intracellular signalling molecules that spread the information to...
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1.8 Protein–protein interactions in signal transduction
Many signalling proteins have both a catalytic domain and sometimes several binding domains.Some only have binding domains, enabling their proteins to act as adaptor, scaffold or anchoring proteins to...
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1.7 Localization of signalling proteins
Since signalling proteins cannot diffuse as rapidly as small second messengers, they need be close to their downstream target in order to be able to function. Where they are located with respect to...
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1.6 Signalling proteins can act as molecular switches
How does a signalling molecule actually convey a signal? With second messengers, it is easy to understand: they are produced or released in large quantities, diffuse to their target, to which they...
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1.5 Signal transduction mechanisms
Signalling information has to be transmitted from the receptor in the plasma membrane across the cytoplasm to the nucleus (if gene transcription is the response), the cytoskeleton (if cell movement, or...
View Article1.4 Cellular responses are diverse
Cellular responses can be extremely rapid – for example, the opening of ion channels to effect a change in the membrane potential or the contraction of muscle fibres, which occur within milliseconds of...
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1.3 Most receptors are on the cell surface
Water-soluble signalling molecules cannot cross the membrane lipid bilayer, but bind to specific receptors embedded in the plasma membrane. The receptors have an extracellular domain that binds the...
View Article1.2.2 Cell–cell signalling via secreted molecules
Extracellular signalling molecules are all fairly small, and are easily conveyed to the site of action; they are structurally very diverse. The classification and individual names of these mainly...
View Article1.2.1 Cell–cell contact-dependent signalling
In some instances, cells may communicate directly with their immediate neighbour through gap junctions (Figure 3a). Communication via gap junctions partially bypasses the signalling model we have...
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1.2 Extracellular signals can act locally or at a distance
First we shall consider the general types of intercellular signalling mechanism within multicellular organisms (Figure 3). Broadly speaking, cells may interact with each other directly, requiring...
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1.1 Introduction
The fundamental principles of signalling can be illustrated by a simple example in the yeast S. cerevisiae (Figure 1). In order to sexually reproduce, a yeast cell needs to be able to make physical...
View ArticleLearning outcomes
By the end of this unit you should be able to:define and use each of the terms printed in bold in the text.understand the basic principles of signal transduction mechanisms, in particular the concepts...
View ArticleIntroduction
Even the simplest organisms can detect and respond to events in their ever-changing environment. Similarly, within a multicellular organism, cells are surrounded by an extracellular environment from...
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