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Signal transduction

 
Sci-Tech Dictionary: signal transduction
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(′sig·nəl tranz′dək·shən)

(cell and molecular biology) The relaying of molecular signals (for example, as contained in a hormone) or physical signals (for example, sensory stimuli) from a cell's exterior to its intracellular response mechanisms.

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Sci-Tech Encyclopedia: Signal transduction
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The transmission of molecular signals from a cell's exterior to its interior. Molecular signals are transmitted between cells by the secretion of hormones and other chemical factors, which are then picked up by different cells. Sensory signals are also received from the environment, in the form of light, taste, sound, smell, and touch. The ability of an organism to function normally is dependent on all the cells of its different organs communicating effectively with their surroundings. Once a cell picks up a hormonal or sensory signal, it must transmit this information from the surface to the interior parts of the cell—for example, to the nucleus. This occurs via signal transduction pathways that are very specific, both in their activation and in their downstream actions. Thus, the various organs in the body respond in an appropriate manner and only to relevant signals. See also Cell (biology).

All signals received by cells first interact with specialized proteins in the cells called receptors, which are very specific to the signals they receive. These signals can be in various forms. The most common are chemical signals, which include all the hormones and neurotransmitters secreted within the body as well as the sensory (external) signals of taste and smell. The internal hormonal signals include steroid and peptide hormones, neurotransmitters, and biogenic amines, all of which are released from specialized cells within the various organs. The external signals of smell, which enter the nasal compartment as gaseous chemicals, are dissolved in liquid and then picked up by specialized receptors. Other external stimuli are first received by specialized receptors (for example, light receptors in the eye and touch receptors in the skin), which then convert the environmental signals into chemical ones, which are then passed on to the brain in the form of electrical impulses.

Once a receptor has received a signal, it must transmit this information effectively into the cell. This is accomplished either by a series of biochemical changes within the cell or by modifying the membrane potential by the movement of ions into or out of the cell. Receptors that initiate biochemical changes can do so either directly via intrinsic enzymatic activities within the receptor or by activating intracellular messenger molecules. Receptors may be broadly classified in four groups that differ in their mode of action and in the molecules that activate them.

The largest family of receptors are the G-protein-coupled receptors (GPCRs), which depend on guanosine triphosphate (GTP) for their function. Many neurotransmitters, hormones, and small molecules bind to and activate specific G-protein-coupled receptors.

A second family of membrane-bound receptors are the receptor tyrosine kinases (RTKs). They function by phosphorylating themselves and recruiting downstream signaling components.

Ion channels are proteins open upon activation, thereby allowing the passage of ions across the membrane. Ion channels are responsive to either ligands or to voltage changes across the membrane, depending on the type of channel. The movement of ions changes the membrane potential, which in turn changes cellular function. See also Biopotentials and ionic currents.

Steroid receptors are located within the cell. They bind cell-permeable molecules such as steroids, thyroid hormone, and vitamin D. Once these receptors are activated by ligand, they translocate to the nucleus, where they bind specific DNA sequences to modulate gene expression. See also Steroid.

The intracellular component of signal propagation, also known as signal transduction, is receptor-specific. A given receptor will activate only very specific sets of downstream signaling components, thereby maintaining the specificity of the incoming signal inside the cell. In addition, signal transduction pathways amplify the incoming signal by a signaling cascade (molecule A activates several molecule B's, which in turn activate several molecule C's) resulting in an appropriate physiological response by the cell.

Several small molecules within the cell act as intracellular messengers. These include cAMP, cyclic guanosine monophosphate (cGMP), nitric oxide (NO), and Ca2+ ions. Increased levels of Ca2+ in the cell can trigger several changes, including activation of signaling pathways, changes in cell contraction and motility, or secretion of hormones or other factors, depending on the cell type. Increased levels of nitric oxide cause relaxation of smooth muscle cells and vasodilation by increasing cGMP levels within the cell. Increasing cAMP levels can modulate signaling pathways by activating the enzyme protein kinase A (PKA).

One of the most important functions of cell signaling is to control and maintain normal physiological balance within the body. Activation of different signaling pathways leads to diverse physiological responses, such as cell proliferation, death, differentiation, and metabolism. Signaling pathways in cells may also interact with each other and serve as signal integrators. For example, negative and positive feedback loops in pathways can modulate signals within a pathway; positive interactions between two signaling pathways can increase duration of signals; and negative interactions between pathways can block signals. See also Cell nucleus; Cell organization; Endocrine system (vertebrate); Noradrenergic system.

Genetics Encyclopedia: Signal Transduction
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To survive, an organism must constantly adjust its internal state to changes in the environment. To track environmental changes, the organism must receive signals. These may be in the form of chemicals, such as hormones or nutrients, or may take another form, such as light, heat, or sound. A signal itself rarely causes a simple, direct chemical change inside the cell. Instead, the signal sets off a chain of events that may involve several or even dozens of steps. The signal is thereby transduced, or changed in form. Signal transduction refers to the entire set of pathways and interactions by which environmental signals are received and responded to by single cells.

Signal transduction systems are especially important in multicellular organisms, because of the need to coordinate the activities of hundreds to trillions of cells. Multicellular organisms have developed a variety of mechanisms allowing very efficient and controlled cell-to-cell communication. Though we take it for granted, it is actually astonishing that our skin, for example, continues to grow at the right rate to replace the continuous loss of its surface every day of our lives. This tight regulation is found in every tissue of our body all of the time, and when this fine control breaks down, cancer may be the result. Clearly the molecular mechanisms behind this astounding level of control must be powerful, versatile, and sophisticated.

Signals, Receptors, and Cascades

The signals that cells use to communicate with one another are often small amino acid chains, called peptides. Depending on the cell type that releases them and the effect they have on the target cell, they may be called hormones, growth factors, neuropeptides, neurotransmitters, or cytokines. Other small molecules can also be signals, such as amino acids and steroids such as testosterone. External signals such as odorants and tastes can be carried to us in the atmosphere or in the fluids of our food and drinks. Stretch, pressure, and other mechanical effects as well as heat, pain, and light can also act as signals.

Given the huge variety of signals to which a cell is exposed, how does it know which to respond to? The answer is that signals are received by protein receptors made by the cell, and a cell is sensitive only to those signals for which it has made receptors. For instance, every cell in the body is exposed to estrogen circulating in the blood, but only a subset of them make estrogen receptors, and are therefore sensitive to its influence.

Chemical signals such as hormones bind to their receptors, usually at the surface of the cell (the plasma membrane), but sometimes within the cell. This causes a conformation (shape) change in the receptor. The conformation change typically alters the ability of the receptor to bind to another molecule in the cell, modifying that molecule's conformation, or triggering other actions.

This sequence of events triggered by the signal-receptor interaction is called a transduction cascade. A transduction cascade involves a network of enzymes that act on one another in specific ways to ultimately generate precise and appropriate responses. These responses may include alterations in cell motility or division, induction of the expression of specific genes, and the regulation of apoptosis. The molecular details of several such cascades are known, but many more undoubtedly remain to be discovered.

The value of this complex cascade of events is severalfold. First, the network of interactions provides many levels of control, so that the cell can tailor the magnitude and timing of its response very finely. Second, the many levels of interaction allow amplification of the original signal to quickly produce a strong response to a small stimulus. For example, there may be only a few hundred copies of a specific receptor on the surface of a typical cell. Activation of even a small percentage of them, acting through these amplifying enzyme cascades, can result in activation of millions of downstream target molecules. This explains how even very small amounts of signals such as growth factor can have such profound effects on appropriately receptive cells.

The Importance of Phosphorylation and Dephosphorylation

After a signal is received, signal transduction involves altering the behavior of proteins in the cascade, in effect turning them on or off like a switch. Adding or removing phosphates is a fundamental mechanism for altering the shape, and therefore the behavior, of a protein. Phosphorylation may open up an enzyme's active site, allowing it to perform chemical reactions, or it may frequently generate a binding site allowing a specific interaction (may make a bulge in one side preventing the protein from fitting together) with a molecular partner.

Enzymes that add phosphate groups to other molecules are called kinases, and the molecules the enzymes act on are called substrates. Protein kinases are a family of enzymes that use ATP to add phosphate groups on to other proteins, thereby altering the properties of these substrate proteins. Protein kinases themselves are frequently turned on or off by phosphorylation performed by other protein kinases; thus a kinase can be both enzyme and substrate.

Protein kinases can be broadly divided into two groups based on the amino acids to which they add phosphate groups. The serine/threonine kinases (ser/thr) are found in all eukaryotic cells and tend to be involved in regulation of metabolic and cytoskeletal activity. The tyrosine (tyr) kinases are found in all animals but not in yeast, protozoa, or plants, and appear to have evolved specifically to deal with the complex challenges of signaling in animals.

Molecular switches are useful only if they can also be flipped back to their original state. This is achieved by specific protein phosphatases, which can remove phosphate groups from kinase substrates.

Signal Transduction: the Rtk Pathway

How does the cell "know" when a particular receptor molecule in the membrane is occupied, and how is that information chemically translated into actions within the cell? Let us examine the signaling pathway for the receptor tyrosine kinases (RTK). The RTKs are a very powerful and important family of signaling molecules and include receptors for potent growth factors and such hormones as insulin, epidermal growth factor, and nerve growth factor.

In this system, the extracellular "ligand" (growth factor or hormone) must crosslink two receptor molecules in order to begin the transduction cascade. The interaction of the two intracellular domains of the receptors then initiates a signaling response.

The simplest RTKs have three parts: a ligand binding site outside the cell, a single membrane-spanning domain, and a tyrosine kinase domain inside the cell. The ligand is typically a diffusible peptide or small protein produced elsewhere in the organism, and in this case is the specific growth factor recognized by the RTK. In the absence of its specific growth factor, this receptor remains unbound to a second receptor, and is inactive. Growth factor, when it arrives, binds to two receptors, cross-linking them. This causes the two tyrosine kinase domains to come into contact with one another. Each kinase now has a substrate, formed by the other receptor, and so each phosphorylates the other on multiple tyrosine sites.

The receptors may now bind with one or more other proteins (called SH2 proteins) that specifically recognize their phosphorylated tyrosines. Many of these are enzymes, while others are adapter molecules that in turn attract and bind other enzymes. Often these enzymes are inactive until they join the receptor complex, because their substrates are found only in the membrane. The products of these enzymes may act on yet other molecules, thus continuing the signaling cascade, or they may be used in cell metabolism for growth or other responses.

Signal Transduction: the Gpcr Pathway and G Proteins

The G protein coupled receptors (GPCR) illustrate another way to receive and interpret a signal, in which the ligand binds to a single transmembrane protein, causing a conformation change and activating "G proteins" inside the cell. G proteins are so named because they have a binding site for guanine nucleotide, either a diphosphate (GDP) or a triphosphate (GTP). Like ATP, GTP is the high-energy form of the nucleotide, while GDP is the low-energy form.

The GPCR family of proteins has at least 300 members in humans. They are specific receptors for numerous neurotransmitters, hormones, peptides and other substances. A large subgroup of these are odorant receptors directly responsible for our senses of taste and smell.

Surprisingly, a further group of GPCRs is responsible for our sense of vision. Opsin molecules, including rhodopsin, are actually GPCRs. Instead of a ligand binding site, rhodopsin has a molecule of retinal bound in the same relative position. Light alters the conformation of the retinal, and rhodopsin responds to this by altering its protein conformation. This causes G protein activation in a similar manner to the other GPCRs.

Each GPCR is associated with a particular type of G protein inside the cell, and there are dozens of different G proteins known. G proteins are generally inactive in the GDP-bound form. They are activated when GDP departs and is replaced by GTP. GTP is found in excess in cells, and so GDP departure is followed rapidly by GTP binding. This causes a profound conformational change, allowing the G protein to interact with and influence numerous target molecules.

Each GPCR associated G protein consists of three parts, the α, β, and γ subunits. The α subunit binds either GDP or GTP. The β and γ subunits are always found together in a complex called Gβγ. In unstimulated cells the whole three-part complex is found in the plasma membrane, with GDP in the binding site.

Binding of ligand to the GPCR causes a conformational change that is transmitted to the cytoplasmic region of the receptor, which interacts with the G protein to dissociate the GDP. This results in GTP binding, which alters the structure of the α subunit, freeing it from Gβγ. Both parts, the Gα(GTP) and the Gβγ, now diffuse away from the receptor and separately interact with and influence many other molecules in the cell.

Second Messengers

One target for certain Gα(GTP) types is the enzyme adenyl cyclase. This enzyme uses ATP to generate cyclic AMP (cAMP). The cAMP molecule is a "second messenger," one of a family of small diffusible substances that powerfully induce cytoplasmic responses.

Cyclic AMP exerts much of its effects by activating the cAMP-dependent protein kinase (PKA), a ser/thr kinase that can phosphorylate and influence many cellular proteins. For example, PKA phosphorylates CREB (cyclic AMP response element binding protein), which is found attached to the promoters of many genes. Phosphorylation of CREB by PKA can thus regulate the expression of these genes.

Another Gα(GTP) target is an enzyme, phospholipase C, which cleaves a membrane lipid called PIP-2. This produces two products: DAG and IP-3. DAG stays in the membrane and binds all members of the ser/thr protein kinase C (PKC) family of enzymes, which may then become activated and phosphorylate and regulate a host of metabolic and structural enzymes. IP-3, another second messenger, rapidly diffuses to IP-3 receptors in the endoplasmic reticulum membrane. When IP-3 binds, it opens channels in the membrane, releasing stored calcium into the cytoplasm. Calcium is normally kept at very low levels in the cytoplasm, and even small increases cause numerous major effects, so that calcium is also regarded as a powerful second messenger. These effects include the activation of various calcium binding proteins such as calmodulin and its many relatives. The calcium-bound versions of these proteins regulate many other enzymes. For example, calcium activates all members of a large and important family of ser/thr kinases called calcium/calmodulin dependent protein kinases (CAM kinases), which themselves regulate the activity of numerous important substrate molecules.

Just as protein kinases need to be turned off, so too do G proteins. This occurs when the GTP on the Gα is cleaved to generate GDP, thus favoring the reformation of the three-part inactive protein.

Interacting Pathways, Defective Signaling, and Treatments for Disease

The GPCR and RTK pathways do not necessarily remain separate, either from each other or from other signaling pathways. One of the most important pathways is directly downstream of RTKs and also many GPCRs, and is called the mitogen activated protein (MAP) kinase cascade. MAP kinase is an abundant ser/thr kinase that, when activated, phosphorylates and powerfully affects the activity of a large number of cytoskeletal, signaling, and nuclear proteins, including an important family of transcription factors, thus directly influencing gene expression.

Both pathways also help regulate a particularly important process called apoptosis. Many cells need specific growth factors to stay alive; the growth factors trigger pathways involving various ser/thr protein kinases that ultimately inactivate molecules that would otherwise promote apoptosis.

The entire signal transduction system normally works astonishingly well, but serious problems can occur. Cancer is unregulated cell growth and occurs when the machinery tightly regulating cell growth breaks down. It is often easy to see how this has occurred. Mutations in growth factor receptors, G proteins, MAP kinases, and other molecules frequently contribute to cancer, and generally result in these molecules losing their normal switching function, staying in the activated form and therefore inappropriately stimulating these important enzyme cascades.

The complexity of the signaling system makes for challenging research, but once understood it holds the promise for better treatments for cancer and other diseases. This is because each step in each pathway provides one or more targets for drugs. Designing a drug that could quiet the excess signaling caused by defective MAP kinase, for example, might provide a promising cancer treatment.

The examples given thus far provide only an outline of how signal transduction cascades work and an overview of a few of the most important enzymes. The actual process is much more complex, and there is much about the process that remains mysterious. Perhaps the biggest mystery is how the cell makes sense of all of the input from different growth factors, hormones, extracellular substrates, and so on to produce an appropriate response. The solution to this problem will result from a complete understanding and computer modeling of the biochemical and kinetic properties of the components of all these signaling cascades.

Bibliography

Alberts, Bruce., et al. Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2002.

Scott, John D., and Tony Pawson. "Cell Communication: The Inside Story." Scientific American (June 2000).

Special Issue on Mapping Cellular Signaling. Science 296, no. 5573 (May 31, 2002).

—Gerry Shaw

Wikipedia: Signal transduction
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Overview of signal transduction pathways

In biology, 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 and 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, or minutes for the activation of protein- and lipid-mediated kinase cascades, but some can take hours, and even days (as is the case with gene expression), to complete. 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.

Contents

History

Occurrence of the term “signal transduction” The total number of papers published in each year since 1977 containing the specific phrase “signal transduction” in either their title or abstract section are plotted. These figures were extracted through an analysis of the papers contained within the MEDLINE database.

The earliest published scientific paper recorded in the MEDLINE database as containing the specific term "signal transduction" within its text was published in 1972.[1] Prior to 1977 articles can be found that use the term "signal transmission" or "sensory transduction" within their title or abstract.[2][3] However, it was not until 1977 that papers began to be published with the specific term "signal transduction" within their abstract; it was not until 1979 that this term appeared within a paper title.[4][5] One source attributes the widespread use of the term signal transduction to a 1980 review article by Rodbell.[6][7]

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[citation needed].

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,[7] 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.[8] 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.[9] 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:

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[17] and small molecules such as serotonin[18] and dopamine.[19] Hormones are also a generic class of molecule able to initiate signal transduction, these include insulin (a polypeptide),[20] testosterone (a steroid),[21] and epinephrine (an amino acid derivative, in essence a small organic molecule).[22]

The classification of one molecule into one class or 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.[citation needed] 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.[citation needed] Thus, sensing of both the external and internal environments at the cellular level relies on signal transduction.[citation needed] 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,[23] odorants binding to odorant receptors in the nasal epithelium,[24] and bitter and sweet tastes stimulating taste receptors in the taste buds.[25] 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.[26] Yeast also use mating factors to determine the mating types of other yeast and participate in sexual reproduction.[27]

Cellular responses

Activation of genes,[28] alterations in metabolism,[29] the continued proliferation and death of the cell,[30] and the stimulation or suppression of locomotion,[31] 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[29] 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.[32]

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.[15] 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,[11] or can be found on the surface of other cells or within the extracellular matrix.[12] 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.[33]

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 disregulation.

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

Types of receptor

Receptors can be roughly divided into two major classes:

  1. Intracellular receptors and
  2. Cell-surface receptors.

Ligand-gated ion channel receptors are a class of receptor that may occur both at the cell-surface or intracellularly.

Receptors that are solely intracellular include those for steroid hormones, thyroid hormone, retinoic acid, and derivatives of vitamin D3. In contrast to ligands that bind to cell surface receptors, in order to initiate signal transduction these ligands must cross the cell membrane. See the intracellular receptors section below for more details.

Cell-surface receptors

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Cell-surface receptors are integral transmembrane proteins and recognize the vast majority of extracellular signaling molecules. Transmembrane receptors span the plasma membrane of the cell, with one part of the receptor on the outside of the cell (the extracellular domain), and the other on the inside of the cell (the intracellular domain). Signal transduction occurs as a result of stimulatory molecule or the binding of a ligand to its extracellular domain; the ligand itself does not pass through the plasma membrane prior to receptor-binding.

Binding of a ligand to a cell-surface receptor stimulates a series of events inside the cell, with different types of receptor stimulation of different intracellular responses. Receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand initiates the transmission of a signal across the plasma membrane by inducing a change in the shape or conformation of the intracellular part of the receptor (see this link [2]for a molecular model for receptor activation). Often, such changes in conformation either result in the activation of an enzymatic activity contained within the receptor or expose a binding site for other signaling proteins within the cell. Once these proteins bind to the receptor, they themselves may become active and propagate the signal into the cytoplasm.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity. These enzymes include tyrosine kinase, heterotrimeric G proteins, small GTPases, various serine/threoine protein kinases, phosphatases, lipid kinases, and hydrolases. Some receptor-stimulated enzymes create specific second messengers including cyclic nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), Phosphatidylinositol derivatives, such as Phosphatidylinositol-triphosphate (PIP3), Diacylglycerol (DAG) and Inositol-triphosphate (IP3), IP3, controlling the release of intracellular calcium stores into the cytoplasm (see second messengers section later in this article). Other activated proteins interact with adapter proteins. Adapter proteins facilitate interactions between other signaling proteins, and coordinate the formation of signaling complexes necessary to produce an appropriate cellular response to a particular stimulus. Enzymes and adapter proteins are both responsive to various second messenger molecules.

Many of the enzymes activated as part of the signal transduction mechanism and also many adapter proteins have been found to possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind specifically to the EF hand domains of calmodulin, allowing this molecule to bind and activate Calmodulin-dependent kinase. PIP3, PIP2 and other phosphoinositides may bind to the Pleckstrin homology domains of proteins such as the kinase protein AKT again with activation activity.

There are many different classes of transmembrane receptor that recognize different extracellular signaling molecules. Specific example receptors discussed in this article are:

  1. G-protein coupled receptors, e.g., Chemokine receptors
  2. Receptor tyrosine kinases, e.g., Growth factor receptors,
  3. Integrins
  4. Toll-like receptors

Further examples are given in the transmembrane receptor article.

G-protein-coupled receptors

For more details on this topic, see G-protein-coupled receptor.
Signal transduction from a G-protein-linked receptor following interaction with its hormone ligand

G-protein-coupled receptors (GPCRs) are a family of integral membrane proteins that possess seven membrane-spanning domains, and are linked to a guanine nucleotide-binding protein (or heterotrimeric G protein). Many receptors make up this family, including adrenergic receptors, neurotransmitter receptors, olfactory receptors, opioid receptors, chemokine receptors, and rhodopsin.

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor. An inactive G protein exists as a heterotrimer, a molecule composed of three different protein subunits: Gα, Gβ, and Gγ. Once the GPCR recognizes a ligand, the shape (conformation) of the receptor changes to mechanically activate the G protein, and causes one subunit (Gα) to bind a molecule of GTP (causing activation) and dissociate from the other two G-protein subunits (Gβ and Gγ). The dissociation exposes sites on the G-protein subunits that interact with other molecules.[34] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins, including phosphodiesterases and adenylyl cyclases, phospholipases, and ion channels that permit the release of second messenger molecules such as cyclic-AMP (cAMP), cyclic-GMP (cGMP), inositol triphosphate (IP3), diacylglycerol (DAG), and calcium (Ca2+) ions.[35] For example, a rhodopsin molecule in the plasma membrane of a retina cell in the eye that was activated by a photon can activate up to 2000 effector molecules (in this case, transducin) per second.

The total strength of signal amplification by a GPCR is determined by:

  • The lifetime of the ligand-receptor-complex. If the ligand-receptor-complex is stable, it takes longer for the ligand to dissociate from its receptor, thus the receptor will remain active for longer and will activate more effector proteins.
  • The amount and lifetime of the receptor-effector protein-complex. The more effector protein is available to be activated by the receptor, and the faster the activated effector protein can dissociate from the receptor, the more effector protein will be activated in the same amount of time.
  • Deactivation of the activated receptor. A receptor that is engaged in a hormone-receptor-complex can be deactivated, either by covalent modification (for example, phosphorylation) or by internalization (see ubiquitin).
  • Deactivation of effectors through intrinsic enzymatic activity. Either small or large G-proteins possess intrinsic GTPase activity, which controls the duration of the triggered signal. This activity may be increased through the action of other proteins such as GTPase-activating proteins (GAPS).

The idea that G-protein-coupled receptors, to be specific, chemokine receptors, participate in cancer development is suggested by a study wherein a point mutation was inserted into the gene encoding the chemokine receptor CXCR2. Cells transfected with the CXCR2 mutant underwent a malignant transformation.[36] The result of the point mutation was the expression of CXCR2 in an active conformation, despite the absence of chemokine-binding (the CXCR2 mutant is said to be "constitutively active").

Receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligand. There are many RTK proteins that are classified into subfamilies depending on their structural properties and ligand specificity. These include many growth factor receptors such as insulin receptor and the insulin-like growth factor receptors, and many others receptors.[37] To conduct their biochemical signals, RTKs need to form dimers in the plasma membrane[38]. The dimer is stabilized by ligand binding by the receptor. Interaction between the two cytoplasmic domains of the dimer is thought to stimulate autophosphorylation of tyrosines within the cytoplasmic tyrosine kinase domains of the RTKs causing their conformational changes. The kinase domain of the receptors is subsequently activated, initiating signaling cascades of phosphorylation of downstream cytoplasmic molecules. These signals are essential to various cellular processes, such as control of cell growth, differentiation, metabolism, and migration.[37]

As is the case with G-Protein-coupled receptors, proteins that bind GTP play a major role in transmission of signal from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as small G proteins. These proteins act as molecular switches that are usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Thus, upon activation, they are responsible for the recruitment of proteins to specific membrane subdomains where they participate in signaling. Activated RTKs, in turn, activate small G proteins, which in turn activate Guanine Nucleotide Exchange Factors, such as SOS1. Once activated, these exchange factors can activate many more small G-proteins, thus amplifying the receptors initial signal.

As with the mutation of G-protein coupled receptors, the mutation of certain RTK genes can result in the expression of receptors that exist in a constitutively-activate state. Such mutated RTK genes may act as oncogenes, genes that contribute to the initiation or progression of cancer.[39]

Integrins

For more details on this topic, see Integrin.
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al (2007).[40]

Integrins are produced by a wide variety of cell types, and play a role in the attachment of a cell to the extracellular matrix (ECM) and to other cells, and in the signal transduction of signals received from extracellular matrix components such as fibronectin, collagen, and laminin. Ligand-binding to the extracellular domain of integrins induces a conformational change within the protein and a clustering of the protein at the cell surface, in order to initiate signal transduction. Integrins lack kinase activity, and integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules such as integrin-linked kinase (ILK), focal-adhesion kinase (FAK), talin, paxillin, parvins, p130Cas, Src-family kinases, and GTPases of the Rho family, the main protein coordinating signal transduction being ILK.[40] As shown in the overview to the right, cooperative integrin and receptor tyrosine kinase signaling determine cellular survival, apoptosis, proliferation, and differentiation.

Important differences exist between integrin-signaling in circulating blood cells and that in non-circulating blood cells such as epithelial cells. Integrins at the cell-surface of circulating cells are inactive under normal physiological conditions. For example, cell-surface integrins on circulating leukocytes are maintained in an inactive state in order to avoid epithelial cell attachment. Only in response to appropriate stimuli are leukocyte integrins converted into an active form, such as those received at the site of an inflammatory response. In a similar manner, it is important that integrins at the cell surface of circulating platelets are kept in an inactive state under normal conditions, in order to avoid thrombosis. Epithelial cells, in contrast, have active integrins at their cell surface under normal conditions, which help to maintain their stable adhesion to underlying stromal cells, which provide appropriate signals in order to maintain their survival and differentiation.[41]

Toll-like receptors

For more details on this topic, see toll-like receptor.

When activated, Toll-like receptors (TLRs) recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram.[42][43][44] The adapters activate other molecules within the cell, including certain protein kinases (IRAK1,IRAK4, TBK1, and IKKi) that amplify the signal, and ultimately lead to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and, together, the TLRs constitute one of the most powerful and important gateways for gene modulation.

Ligand-gated ion channel receptors

For more details on this topic, see ligand gated ion channel.

A ligand-activated ion channel will recognize its ligand, and then undergo a structural change that opens a gap (channel) in the plasma membrane through which ions can pass. These ions will then relay the signal. An example for this mechanism is found in the receiving cell, or post-synaptic cell of a neural synapse.

By contrast, other ion channels open in response to a change in cell potential, that is, the difference of the electrical charge across the membrane. In neurons, this mechanism underlies the action potentials that travel along nerves. The influx of ions that occurs in response to ligand-gated ion channels often induce action potentials by depolarizing the membrane of the post-synaptic cells, which results in the wave-like opening of voltage-gated ion channels. In addition, calcium ions are also commonly allowed into the cell during ligand-induced ion channel opening. This calcium can act as a classical second messenger, setting in motion signal transduction cascades and altering the cellular physiology of the responding cell. This may result in strengthening of the synapse between the pre- and post-synaptic cells by remodeling the dendritic spines involved in the synapse.

Intracellular receptors

Further information: Intracellular receptor

Intracellular receptors include nuclear receptors and cytoplasmic receptors, and are soluble proteins localized within the nucleoplasm or the cytoplasm, respectively. The typical ligands for nuclear receptors are lipophilic hormones, with steroid hormones (for example, testosterone, progesterone, and cortisol) and derivatives of vitamin A and D among them. In order to reach its receptor and initiate signal transduction, the hormone must pass through the plasma membrane, usually by passive diffusion. The nuclear receptors are ligand-activated transcription activators; on binding with the ligand (the hormone), the ligands will pass through the nuclear membrane into the nucleus and enable the transcription of a certain gene and, thus, the production of a protein.

The nuclear receptors that were activated by the hormones attach at the DNA at receptor-specific Hormone-Responsive Elements (HREs), DNA sequences that are located in the promoter region of the genes that are activated by the hormone-receptor complex. As this enables the transcription of the according gene, these hormones are also called inductors of gene expression. The activation of gene transcription is much slower than signals that directly affect existing proteins. As a consequence, the effects of hormones that use nucleic receptors are usually long-term. Although the signal transduction via these soluble receptors involves only a few proteins, the details of gene regulation are yet not well understood. The nucleic receptors all have a similar, modular structure:

N-AAAABBBBCCCCDDDDEEEEFFFF-C

where CCCC is the DNA-binding domain that contains zinc fingers, and EEEE the ligand-binding domain. The latter is also responsible for dimerization of most nuclearic receptors prior to DNA binding. As a third function, it contains structural elements that are responsible for transactivation, used for communication with the translational apparatus. The zinc fingers in the DNA-binding domain stabilize DNA binding by holding contact to the phosphate backbone of the DNA. The DNA sequences that match the receptor are usually hexameric repeats, either normal, inverted, or everted. The sequences are quite similar, but their orientation and distance are the parameters by which the DNA-binding domains of the receptors can tell them apart.

Steroid receptors are a subclass of nuclear receptors, located primarily within the cytosol. In the absence of steroid hormone, the receptors cling together in a complex called an aporeceptor complex, which also contains chaperone proteins (also known as heatshock proteins or Hsps). The Hsps are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence that enables its passage into the nucleus is accessible.
Steroid receptors can also have a repressive effect on gene expression, when their transactivation domain is hidden so it cannot activate transcription. Furthermore, steroid receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal end, as a result of another signal transduction pathway, for example, a by a growth factor. This behaviour is called crosstalk.

RXR- and orphan-receptors These nuclear receptors can be activated by

  • a classic endocrine-synthesized hormone that entered the cell by diffusion
  • a hormone that was built within the cell (for example, retinol) from a precursor or prohormone, which can be brought to the cell through the bloodstream
  • a hormone that was completely synthesized within the cell, for example, prostaglandin.

These receptors are located in the nucleus and are not accompanied by chaperone proteins. In the absence of hormone, they bind to their specific DNA sequence, repressing the gene. Upon activation by the hormone, they activate the transcription of the gene that they were repressing.

Certain intracellular receptors of the immune system are examples of cytoplasmic receptors. Recently-identified NOD like receptors (NLRs) reside in the cytoplasm of specific eukaryotic cells and interact with particular ligands, such as microbial molecules, using a leucine-rich repeat (LRR) motif that is similar to the ligand-binding motif of the extracellular receptors known as TLRs. Some of these molecules (e.g., NOD1 and NOD2) interact with an enzyme called RICK kinase (or RIP2 kinase) that activates NF-κB signaling, whereas others (e.g., NALP3) interact with inflammatory caspases (e.g., caspase 1) and initiate processing of particular cytokines (e.g., interleukin-1β).[45] Similar receptors exist inside plant cells and are called Plant R Proteins. Another type of cytoplasmic receptor also has a role in immune surveillance. These receptors are known as RNA Helicases and include RIG-I, MDA5, and LGP2.[46]

Second messengers

Intracellular signal transduction is largely carried out by second messenger molecules.

Calcium

Ca2+ concentration is usually maintained at a very low level in the cytosol by sequestration in the smooth endoplasmic reticulum and the mitochondria. Ca2+ release from the endoplasmic reticulum into the cytosol results in the binding of the released Ca2+ to signaling proteins that are then activated. There are two combined receptor/ion channel proteins that perform the task of controlled transport of Ca2+:

  • The InsP3-receptor will transport Ca2+ upon interaction with inositol triphosphate (thus the name) on its cytosolic side. It consists of four identical subunits.
  • The ryanodine receptor is named after the plant alkaloid ryanodine. It is similar to the InsP3 receptor and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+. It is especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic-ADP ribose) takes part in the receptor activation. The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. Once released into the cytosol from intracellular stores or extracellular sources, Ca2+ acts as a signal molecule within the cell. This works by tightly limiting the time and space when Ca2+ is free (and thus active). Therefore, the concentration of free Ca2+ within the cell is usually very low; it is stored within organelles, usually the endoplasmic reticulum (sarcoplasmic reticulum in muscle cells), where it is bound to molecules like calreticulin.

Ca2+ is used in a multitude of processes, among them muscle contraction, release of neurotransmitter from nerve endings, vision in retina cells, proliferation, secretion, cytoskeleton management, cell migration, gene expression, and metabolism. The three main pathways that lead to Ca2+ activation are :

  1. G protein-regulated pathways
  2. Pathways regulated by receptor-tyrosine kinases
  3. Ligand- or current-regulated ion channels

There are two different ways by which Ca2+ can regulate proteins:

  1. A direct recognition of Ca2+ by the protein
  2. Binding of Ca2+ in the active site of an enzyme.

One of the best-studied interactions of Ca2+ with a protein is the regulation of calmodulin by Ca2+. Calmodulin itself can regulate other proteins, or be part of a larger protein (for example, phosphorylase kinase). The Ca2+/calmodulin complex plays an important role in proliferation, mitosis, and neural signal transduction.

Lipophilic

Lipophilic second messenger molecules are derived from lipids that normally reside in cellular membranes. Enzymes stimulated by activated receptors modify the lipids, converting them into second messengers.

Diacylglycerol is a lipophilic second messenger, required for the activation of protein kinase C. Ceramide, the eicosanoids, and lysophosphatidic acid are also lipophilic second messengers.

Nitric oxide

Nitric oxide (NO) can act as a second messenger. Nitric oxide gas is a free radical that diffuses through the plasma membrane and affects nearby cells. NO is made from arginine and oxygen by the enzyme NO synthase, with citrulline as a by-product. NO works mainly through activation of its target receptor, the enzyme soluble guanylate cyclase, which, when activated, produces the second messenger cyclic-guanosine monophosphate (cGMP). NO can also act through covalent modification of proteins or their metal co-factors. Some of these modifications are reversible and work through a redox mechanism. NO is toxic in high concentrations, and is thought to cause damages caused by stroke.

NO is involved in a number of functions, including relaxation of blood vessels; regulation of exocytosis of neurotransmitters; cellular immune response; modulation of the Hair Cycle; production and maintenance of penile erections; and activation of apoptosis by initiating signals that lead to H2AX phosphorylation.

Major pathway examples

Mechanism of cAMP dependent signaling. In this figure, the neurotransmitter epinephrine (adrenaline) and its receptor (pink) is used as an example. The activated receptor releases the Gs alpha protein (tan) from the beta amd gamma subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger cAMP.[47]
  • MAPK/ERK pathway: A pathway that couples intracellular responses to the binding of growth factors to cell surface receptors. This pathway is very complex and includes many protein components [48]. The basic pathway shown in the figure (to the right) and described below includes the major components of the pathway. In many cell types, activation of this pathway promotes cell division.

See also

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