Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalysed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used.
The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a signaling cascade, which is a chain of biochemical events along a signaling pathway. When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events.
At the molecular level, such responses include changes in the transcription or translation of genes, and post-translational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes. In multicellular organisms, signal transduction pathways have evolved to regulate cell communication in a wide variety of ways.
Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. Ligands are termed first messengers, while receptors are the signal transducers, which then activate primary effectors.
Simplified representation of major signal transduction pathways in mammals. Credit: cybertory CC BY-SA 3.0
Such effectors are often linked to second messengers, which can activate secondary effectors, and so on. Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signalling molecule can generate a response involving hundreds to millions of molecules.
As with other signals, the transduction of biological signals is characterized by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological. With the advent of computational biology, the analysis of signaling pathways and networks has become an essential tool to understand cellular functions and disease, including signalling rewiring mechanisms underlying responses to acquired drug resistance.
Signal Transduction Stimuli
The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition.
Traditionally, signals that reach the central nervous system are classified as senses. These are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.
The majority of signal transduction pathways involve the binding of signalling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signalling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation.
Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors. These include growth factors, cytokines and neurotransmitters.
Components of the extracellular matrix such as fibronectin and hyaluronan can also bind to such receptors (integrins and CD44, respectively). In addition, some molecules such as steroid hormones are lipid-soluble and thus cross the plasma membrane to reach nuclear receptors. In the case of steroid hormone receptors, their stimulation leads to binding to the promoter region of steroid-responsive genes.
Not all classifications of signalling molecules take into account the molecular nature of each class member. For example, odorants belong to a wide range of molecular classes, as do neurotransmitters, which range in size from small molecules such as dopamine to neuropeptides such as endorphins.
Moreover, some molecules may fit into more than one class, e.g. epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla.
Some receptors such as HER2 are capable of ligand-independent activation when overexpressed or mutated. This leads to constituitive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other EGFRs, constituitive activation leads to hyperproliferation and cancer.
The prevalence of basement membranes in the tissues of Eumetazoans means that most cell types require attachment to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum.
Such signaling is mainly orchestrated in focal adhesions, regions where the integrin-bound actin cytoskeleton detects changes and transmits them downstream through YAP1.
Cellular and systemic control of osmotic pressure (the difference in osmolarity between the cytosol and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction).
These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors are transient receptor potential channels present in the primary cilium of human cells. In yeast, the HOG pathway has been extensively characterised.
Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, the heat-shock response. Such response is triggered when high temperatures cause the dissociation of inactive HSF1 from complexes with heat shock proteins Hsp40/Hsp70 and Hsp90.
With help from the ncRNA hsr1, HSF1 then trimerizes, becoming active and upregulating the expression of its target genes. Many other thermosensory mechanisms exist in both prokaryotes and eukaryotes.
First messengers are the signaling molecules (hormones, neurotransmitters, and paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response.
In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.
The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding to signaling proteins that are then activated; it is then sequestered in the smooth endoplasmic reticulum and the mitochondria.
Two combined receptor/ion channel proteins control the transport of calcium: the InsP3-receptor that transports calcium upon interaction with inositol triphosphate on its cytosolic side; and the ryanodine receptor named after the alkaloid ryanodine, similar to the InsP3 receptor but having a feedback mechanism that releases more calcium upon binding with it. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its free state concentration is very low and is mostly bound to organelle molecules like calreticulin when inactive.
Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings, and cell migration. The three main pathways that lead to its activation are GPCR pathways, RTK pathways, and gated ion channels; it regulates proteins either directly or by binding to an enzyme.
Lipophilic second messenger molecules are derived from lipids residing in cellular membranes; enzymes stimulated by activated receptors activate the lipids by modifying them.
Examples include diacylglycerol and ceramide, the former required for the activation of protein kinase C.
Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through activation of soluble guanylyl cyclase, which when activated produces another second messenger, cGMP.
NO can also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage during stroke, but is the cause of many other functions like relaxation of blood vessels, apoptosis, and penile erections.
In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process called redox signaling. Examples include superoxide, hydrogen peroxide, carbon monoxide, and hydrogen sulfide.
Redox signaling also includes active modulation of electronic flows in semiconductive biological macromolecules.
Bradshaw, Ralph A.; Dennis, Edward A., eds. (2010) Handbook of Cell Signaling (2nd ed.) Amsterdam, Netherlands: Academic Press. ISBN 9780123741455