Signal transduction Animation

Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. Most processes of signal transduction involve ordered sequences of biochemical reactions inside the cell, which are carried out by enzymes, activated by second messengers, resulting in a signal transduction pathway. Such processes are usually rapid, lasting on the order of milliseconds in the case of ion flux, minutes for the activation of protein- and lipid-mediated kinase cascades, or hours and even days for gene expression. The number of proteins and other molecules participating in the events involving signal transduction increases as the process emanates from the initial stimulus, resulting in a "signal cascade," beginning with a relatively small stimulus that elicits a large response. This is referred to as amplification of the signal.
Signal transduction

The earliest published scientific paper recorded in the MEDLINE database as containing the specific term "signal transduction" within its text was published in 1972. Prior to 1977 articles can be found that use the term "signal transmission" or "sensory transduction" within their title or abstract. However, it is not until 1977 that papers start to appear with the specific term "signal transduction" within their abstract, and 1979 before this specific term appears within a paper title. One source attributes the widespread use of the term signal transduction to a 1980 review article by Rodbell.

As can be seen from the graph to the right, it is not until the late 1980s/early 1990s that research papers directly addressing signal transduction processes began to appear in large numbers in the scientific literature. The occurrence of a specific term within the title or abstract of a scientific paper is usually a good indicator that the paper addresses a specifically related area of research. While there may be considered to be a number of landmark or important discoveries in the field of signal transduction, such as the link made by Rodbell between metabolic regulation and the activity of GTP and GTP-binding proteins, much of our current understanding of signal transduction processes is as a result of numerous contributions made to the field over many years by different research groups all over the world.

The total number of scientific papers related to signal transduction published since 1st Jan 1977 up to the 31st December 2007 was 48,377 of which only 11,211 were reviews of other papers

Signaling Molecules

Most signal transduction involves the binding of extracellular signaling molecules (or ligands) to cell-surface receptors that face outward from the plasma membrane and trigger events inside the cell. Also, intracellular signaling cascades can be triggered through cell-substratum interactions, as in the case of integrins, which bind ligands found within the extracellular matrix. Steroids represent another example of extracellular signaling molecules that may cross the plasma membrane due to their lipophilic or hydrophobic nature.Many, but not all, steroids have receptors within the cytoplasm, and usually act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.Within multicellular organisms, there is a diverse number of small molecules and polypeptides that serve to coordinate a cell's individual biological activity within the context of the organism as a whole. These molecules have been functionally classified as:

* hormones (e.g., melatonin),
* growth factors (e.g. epidermal growth factor),
* extra-cellular matrix components (e.g., fibronectin),
* cytokines (e.g., interferon-gamma),
* chemokines (e.g., RANTES),
* neurotransmitters (e.g., acetylcholine), and
* neurotrophins (e.g., nerve growth factor).

It is important to note that most of these classifications do not take into account the molecular nature of each class member. For example, as a class, neurotransmitters consist of neuropeptides such as endorphins and small molecules such as serotonin and dopamine.Hormones are also a generic class of molecule able to initiate signal transduction, these include insulin (a polypeptide),testosterone (a steroid), and epinephrine (an amino acid derivative, in essence a small organic molecule).

The classification of one molecule into one class of another is not exact. For example, epinephrine and norepinephrine secreted by the central nervous system act as neurotransmitters. However, epinephrine when secreted by the adrenal medulla acts as a hormone.

Environmental stimuli
In bacteria and other single-cell organisms, the variety of a signal transduction processes of which the cell is capable influences how many ways it can react and respond to its environment. In multicellular organisms, a multitude of different signal transduction processes are required for coordinating the behavior of individual cells to support the function of the organism as a whole. As may be expected, the more complex the organism, the more complex the repertoire of signal transduction processes the organism must possess. Thus, sensing of both the external and internal environments at the cellular level relies on signal transduction. Many disease processes such as diabetes, heart disease, autoimmunity, and cancer arise from defects in signal transduction pathways, further highlighting the critical importance of signal transduction to biology, as well as medicine.

In addition to many of the regular signal transduction stimuli listed above, in complex organisms, there are also examples of additional environmental stimuli that initiate signal transduction processes. Environmental stimuli may also be molecular in nature (as above) or more physical, such as light striking cells in the retina of the eye, odorants binding to odorant receptors in the nasal epithelium, and bitter and sweet tastes stimulating taste receptors in the taste buds. Certain microbial molecules, e.g., viral nucleotides, bacterial lipopolysaccharides, and protein antigens, are able to elicit an immune system response against invading pathogens, mediated via signal transduction processes. An immune response may occur independent of signal transduction stimulation by other molecules, as is the case for signal transduction via the Toll-like receptor or with help from stimulatory molecules located at the cell surface of other cells, as is the case for T-cell receptor signaling.

Unicellular organisms may also respond to environmental stimuli via the activation of signal transduction pathways. For example, slime molds secrete cyclic-AMP upon starvation, which stimulates individual cells in the immediate environment to aggregate. Yeast also use mating factors to determine the mating types of other yeast and participate in sexual reproduction.

Cellular responses
Activation of genes, alterations in metabolism, the continued proliferation and death of the cell, and the stimulation or suppression of locomotion,are some of the cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the protein products of many of the responding genes include enzymes and transcription factors themselves. Transcription factors produced as a result of a signal transduction cascade can, in turn, activate yet more genes. Therefore an initial stimulus can trigger the expression of an entire cohort of genes, and this, in turn, can lead to the activation of any number of complex physiological events. These events include the increased uptake of glucose from the blood stream stimulated by insulin and the migration of neutrophils to sites of infection stimulated by bacterial products. The set of genes and the order in which they are activated in response to stimuli are often referred to as a genetic program.

Neurotransmitters are ligands that are capable of binding to ion channel proteins, resulting in their opening to allow the rapid flow of a particular ion across the plasma membrane. This results in an altering of the cell's membrane potential and is important for processes such as the neural conduction of electrochemical impulses. Ligands can be freely soluble, or can be found on the surface of other cells or within the extracellular matrix. Such cell surface or extracellular matrix ligands signal between cells when they come in contact with each other, such as when a phagocytic cell presents antigens to lymphocytes, or upon adhesion to the extracellular matrix, as when integrins at the cell surface of fibroblasts engage fibronectin.

Most mammalian cells require stimulation to control not only cell division but also survival. In the absence of growth factor stimulation, programmed cell death ensues in most cells. Such requirements for extra-cellular stimulation are necessary for controlling cell behavior in the context of both unicellular and multi-cellular organisms. Signal transduction pathways are perceived to be so central to biological processes that it is not surprising that a large number of diseases have been attributed to their dysregulation.

Discussed below are how signal transduction via various classes of receptor may lead to the above cellular responses.

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