Share on Facebook Share on Twitter Email
Answers.com

Signal transduction

 
McGraw-Hill Science & Technology Dictionary:

signal transduction

Home > Library > Science > Sci-Tech Dictionary
(′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.

Search unanswered questions...

Enter a question here...
Search: All sources Community Q&A Reference topics

McGraw-Hill Science & Technology Encyclopedia:

Signal transduction

Top
Home > Library > Science > Sci-Tech Encyclopedia

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.

Gale Genetics Encyclopedia:

Signal Transduction

Top
Home > Library > Health > Genetics Encyclopedia

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

Oxford Dictionary of Biochemistry:

signal transduction

Top
Home > Library > Science > Biochemistry Dictionary

the process by which an extracellular signal (chemical, electrical, or mechanical) is converted into a cellular response. Typically, interaction of a hormone, growth factor, or other agonist with a specific membrane receptor leads to signal amplification by synthesis within the cell of one or more second messengers, or to activation of other downstream cascades, e.g. by phosphorylation of proteins. Chemical agonists that cross the cell membrane (e.g. steroid hormones) produce a cellular response without such amplification of the signal. Electrical signals flowing down axonal membranes lead to release of neurotransmitters at synapses. Their plasma membrane receptors are similar to those for hormones and growth factors, or are ion channels. For phototransduction see photosynthesis, visual cascade.

Previous:signal recognition particle receptor, signal recognition particle, signal peptide protease
Next:signal-to-noise ratio, signalling molecule, signature database
Wikipedia on Answers.com:

Signal transduction

Top
Home > Library > Miscellaneous > Wikipedia
 This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (May 2011)
An overview of major signal transduction pathways.

Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response.[1] There are two stages in this process:

  1. A signaling molecule activates a specific receptor on the cell membrane
  2. Causing a second messenger to continue the signal into the cell and elicit a physiological response.

In either step, the signal can be amplified. Thus, one signalling molecule can cause many responses.[2]

Contents

History

Occurrence of the term signal transduction in papers since 1977. These figures were extracted through an analysis of the papers contained within the MEDLINE database.

In 1970, Martin Rodbell examined the effects of glucagon on a rat's liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell's metabolism. Thus he deduced that the G-protein was a transducer that accepted glucagon molecules and affected the cell.[3] For this he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman. The current understanding of signal transduction processes reflects contributions made by Rodbell and many other research groups.

The earliest scientific paper recorded in the MEDLINE database as containing the specific term signal transduction was published in 1972.[4] Some articles published before 1977 used the term signal transmission or sensory transduction for signal transduction:[5][6] a total of 48,377 scientific papers related to signal transduction were published in 1977, of which 11,211 were reviews of other papers. That year the actual term signal transduction was included in abstracts until in 1979 it appeared in a paper's title.[7][8] One source attributes the widespread use of this term to a 1980 review article by Rodbell:[9][3] research papers directly addressing signal transduction processes began to appear in large numbers in the late 1980s and early 1990s.[10]

Signal transduction involves the binding of extracellular signalling molecules and ligands to cell-surface receptors that trigger events inside the cell. The combination of messenger with receptor causes a change in the conformation of the receptor, known as receptor activation. This activation is always the initial step (the cause) leading to the cell's ultimate responses (effect) to the messenger. Despite the myriad of these ultimate responses, they are all directly due to changes in particular cell proteins. Intracellular signaling cascades can be started through cell-substratum interactions; examples are the integrin that binds ligands in the extracellular matrix and steroids.[11] Most steroid hormones have receptors within the cytoplasm and act by stimulating the binding of their receptors to the promoter region of steroid-responsive genes.[12] Examples of signaling molecules include the hormone melatonin,[13] the neurotransmitter acetylcholine[14] and the cytokine interferon γ.[15]

The classifications of signalling molecules do not take into account the molecular nature of each class member; neurotransmitters range in size from small molecules such as dopamine[16] to neuropeptides such as endorphins.[17] Some molecules may fit into more than one class; for example, epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla.

Environmental stimuli

With single-celled organisms, the variety of signal transduction processes influence its reaction to its environment.[citation needed] With multicellular organisms, numerous processes are required for coordinating individual cells to support the organism as a whole; the complexity of these processes tend to increase with the complexity of the organism.[citation needed] Sensing of environments at the cellular level relies on signal transduction;[citation needed] many disease processes, such as diabetes and heart disease arise from defects in these pathways, highlighting the importance of this process in biology and medicine.

Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include photons hitting cells in the retina of the eye,[18] and odorants binding to odorant receptors in the nasal epithelium.[19] Certain microbial molecules, such as viral nucleotides and protein antigens, can elicit an immune system response against invading pathogens mediated by signal transduction processes. This may occur independent of signal transduction stimulation by other molecules, as is the case for the toll-like receptor. It may occur with help from stimulatory molecules located at the cell surface of other cells, as with T-cell receptor signaling. Single-celled organisms may respond to environmental stimuli through the activation of signal transduction pathways. For example, slime molds secrete cyclic adenosine monophosphate upon starvation, stimulating individual cells in the immediate environment to aggregate,[20] and yeast cells use mating factors to determine the mating types of other cells and to participate in sexual reproduction.[21]

Receptors

Receptors can be roughly divided into two major classes: intracellular receptors and extracellular receptors.

Extracellular

Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the conformation of the inside part of the receptor.[22] These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.

In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adapter proteins that facilitate signalling protein interactions and coordination of signalling complexes necessary to respond to a particular stimulus. Enzymes and adapter proteins are both responsive to various second messenger molecules.

Many adapter proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.

G protein-coupled

For more details on this topic, see G-protein-coupled receptor.

G protein-coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. Many receptors are in this family, including adrenergic receptors and chemokine receptors.

Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; it exists as a heterotrimer consisting of Gα, Gβ, and Gγ. Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules.[23] The activated G protein subunits detach from the receptor and initiate signalling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules.[24] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity.

A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors participate in cancer development.[25]

Tyrosine and histidine kinase

Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor.[26] To perform signal transduction, RTKs need to form dimers in the plasma membrane;[27] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosines within the domains of the RTKs, causing conformational changes. The receptors' kinase domains are subsequently activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism.[26]

As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction 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. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively-activate state; such mutated genes may act as oncogenes.[28]

Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.[29]

Integrin

For more details on this topic, see Integrin.
An overview of integrin-mediated signal transduction, adapted from Hehlgens et al. (2007).[30]

Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase.[30] As shown in the picture to the right, cooperative integrin-RTK signalling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.

Important differences exist between integrin-signalling in circulating blood cells and non-circulating cells such as epithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are only activated in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.[31]

Toll gate

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

When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM.[32][33][34] These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1, and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.

Ligand-gated ion channel

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

A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to these channels opening induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.

An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.

Intracellular

Further information: Intracellular receptor

Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are lipophilic hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, enabling gene transcription and protein production.

Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to them enabling gene transcription, they are alternatively called inductors of gene expression. Activation of gene transcription is slower than signals directly affecting existing proteins; therefore, the effects of hormones that use nucleic receptors are long-term.

Signal transduction via these receptors involves little proteins, but the details of gene regulation by this method are not well understood. Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.

Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol; in the absence of steroids, they cling together in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden; activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.

Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs; they repress their gene by binding to their specific DNA sequence when no ligand binds to them and vice versa.

Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates NF-κB signaling, whereas others like NALP3 interact with inflammatory caspases and initiate processing of particular cytokines like interleukin-1β.[35] [36]

Second messengers

First messengers are the intracellular chemical messengers (hormones, neurotransmitters, and panacrine/autocrine agents) which reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances which enter the cytoplasm and act within the cell to trigger a response. Second messengers essentially serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.

Calcium

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.

Lipophilics

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

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 erections.

Redox Signaling

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 [37].

Cellular responses

Gene activations[38] and metabolism alterations[39] are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream[39] and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.[40]

Mammalian cells require stimulation for cell division and survival; in the absence of growth factor, apoptosis ensues. Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and multicellular organisms; signal transduction pathways are perceived to be so central to biological processes that a large number of diseases are attributed to their disregulation.

Major pathways

Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses.

  • IP3/DAG pathway: PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3).  DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol.  IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER).  These channels are specific to calcium and only allow the passage of calcium to move through.  This causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and activity.[43]  In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate other molecules, leading to altered cellular activity.  End effects include taste, manic depression, tumor promotion, etc.[43]

See also

References

  1. ^ Silverthorn (2007). Human Physiology. 4th ed.
  2. ^ Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5. 
  3. ^ a b Rodbell, M. (1980). "The role of hormone receptors and GTP-regulatory proteins in membrane transduction". Nature 284 (5751): 17–22. doi:10.1038/284017a0. PMID 6101906. 
  4. ^ Rensing, L. (1972). "Periodic geophysical and biological signals as Zeitgeber and exogenous inducers in animal organisms". Int. J. Biometeorol. 16: Suppl:113–125. PMID 4621276. 
  5. ^ Tonndorf J. (1975). "Davis-1961 revisited.  Signal transmission in the cochlear hair cell-nerve junction". Arch. Otolaryngol. 101 (9): 528–535. PMID 169771. 
  6. ^ Ashcroft SJ, Crossley JR, Crossley PC. (1976). "The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in the rat". Biochem. J. 154 (3): 701–707. PMC 1172772. PMID 782447. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1172772. 
  7. ^ Hildebrand E. (1977). "What does Halobacterium tell us about photoreception?". Biophys. Struct. Mech. 3 (1): 69–77. doi:10.1007/BF00536457. PMID 857951. 
  8. ^ Kenny JJ, Martinez-Maza O. et al (1979). "Lipid synthesis: an indicator of antigen-induced signal transduction in antigen-binding cells". J. Immunol. 112 (4): 1278–1284. PMID 376714. 
  9. ^ Gomperts, BD.; Kramer, IM. Tatham, PER. (2002). Signal transduction. Academic Press. ISBN 0-12-289631-9. 
  10. ^ Vander "et al" (1998). Human Physiology. McGraw-Hill. pp. 159. ISBN 0-07-067065-X. 
  11. ^ Beato M, Chavez S and Truss M (1996). "Transcriptional regulation by steroid hormones". Steroids 61 (4): 240–251. doi:10.1016/0039-128X(96)00030-X. PMID 8733009. 
  12. ^ Hammes SR (2003). "The further redefining of steroid-mediated signaling". Proc Natl Acad Sci USA 100 (5): 21680–2170. doi:10.1073/pnas.0530224100. PMC 151311. PMID 12606724. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=151311. 
  13. ^ Sugden D, Davidson K. et al. (2004). "Melatonin, melatonin receptors and melanophores: a moving story". Pigment Cell Res. 17 (5): 454–460. doi:10.1111/j.1600-0749.2004.00185.x. PMID 15357831. 
  14. ^ Kistler J, Stroud RM et al. (1982). "Structure and function of an acetylcholine receptor". Biophys. J. 37 (1): 371–383. Bibcode 1982BpJ....37..371K. doi:10.1016/S0006-3495(82)84685-7. PMC 1329155. PMID 7055628. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1329155. 
  15. ^ Schroder et al. (2004). "Interferon-γ an overview of signals, mechanisms and functions". Journal of Leukocyte Biology 75 (2): 163–189. doi:10.1189/jlb.0603252. PMID 14525967. http://www.jleukbio.org/cgi/content/full/75/2/163. 
  16. ^ Missale C, Nash SR. et al (1998). "Dopamine receptors:from structure to function". Physiol. Rev. 78 (1): 189–225. PMID 9457173. 
  17. ^ Goldstein, A. (1976). "Opioid peptides endorphins in pituitary and brain". Science 193 (4258): 1081–1086. doi:10.1126/science.959823. PMID 959823. 
  18. ^ Burns ME and Arshavsky VY. (2005). "Beyond counting photons: trials and trends in vertebrate visual transduction". Neuron 48 (3): 387–401. doi:10.1016/j.neuron.2005.10.014. PMID 16269358. 
  19. ^ Ronnett GV and Moon C. (2002). "G proteins and olfactory signal transduction". Annu Rev Physiol 64 (1): 189–222. doi:10.1146/annurev.physiol.64.082701.102219. PMID 11826268. 
  20. ^ Hanna MH, Nowicki JJ and Fatone MA (1984). "Extracellular cyclic AMP (cAMP) during development of the cellular slime mold Polysphondylium violaceum: comparison of accumulation in the wild type and an aggregation-defective mutant". J Bacteriol 157 (2): 345–349. PMID 215252. 
  21. ^ Sprague GF Jr. (1991). "Signal transduction in yeast mating: receptors, transcription factors, and the kinase connection". Trends Genet 7 (11–12): 393–398. doi:10.1016/0168-9525(91)90218-F. PMID 1668192. 
  22. ^ A molecular model for receptor activation
  23. ^ Jeremy M. Berg, John L. Tymoczko, Lubert Stryer; Web content by Neil D. Clarke (2002). Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4954-8. 
  24. ^ Yang W, Xia S (2006). "Mechanisms of regulation and function of G-protein-coupled receptor kinases". World J Gastroenterol 12 (48): 7753–7. PMID 17203515. 
  25. ^ Burger M, Burger, JA et al (1999). "Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor". J. Immunol. 163 (4): 2017–2022. PMID 10438939. 
  26. ^ a b Li E, Hristova K (2006). "Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies". Biochemistry 45 (20): 6241–51. doi:10.1021/bi060609y. PMID 16700535. 
  27. ^ Schlessinger, J. (1988). "Signal transduction by allosteric receptor oligomerization". Trends Biochem Sci 13 (11): 443–7. doi:10.1016/0968-0004(88)90219-8. PMID 3075366. 
  28. ^ Roskoski, R, Jr. (2004). "The ErbB/HER receptor protein-tyrosine kinases and cancer". Biochem. Biophys. Res. Commun. 319 (1): 1–11. doi:10.1016/j.bbrc.2004.04.150. PMID 15158434. 
  29. ^ Wolanin PW, Thomason PA, Stock JB (2002). "Histidine protein kinases: key signal transducers outside the animal kingdom". Genome Biology 3 (10): reviews3013.1–3013.8. doi:10.1186/gb-2002-3-10-reviews3013. PMC 244915. PMID 12372152. http://genomebiology.com/2002/3/10/reviews/3013. 
  30. ^ a b Hehlgans, S. Haase, M. and Cordes, N. (2007). "Signaling via integrins: Implications for cell survival and anticancer strategies". Biochim. Biophys. Acta. 1775 (1): 163–180. doi:10.1016/j.bbcan.2006.09.001. PMID 17084981. 
  31. ^ Gilcrease MZ. (2006). "Integrin signaling in epithelial cells". Cancer Lett. 247 (1): 1–25. doi:10.1016/j.canlet.2006.03.031. PMID 16725254. 
  32. ^ Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003). "Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway". Science 301 (5633): 640–3. doi:10.1126/science.1087262. PMID 12855817. 
  33. ^ Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003). "TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway". Nat Immunol 4 (11): 1144–50. doi:10.1038/ni986. PMID 14556004. 
  34. ^ Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S (2002). "Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4". Nature 420 (6913): 324–9. doi:10.1038/nature01182. PMID 12447441. 
  35. ^ Delbridge L, O'Riordan M (2007). "Innate recognition of intracellular bacteria". Curr Opin Immunol 19 (1): 10–6. doi:10.1016/j.coi.2006.11.005. PMID 17126540. 
  36. ^ Vander "et al" (1998). Human Physiology. McGraw-Hill. pp. 160. ISBN 0-07-067065-X. 
  37. ^ Forman, H.J., Signal transduction and reactive species. Free Radic. Biol. Med. 47:1237-1238; 2009
  38. ^ Lalli E and Sassone-Corsi P (1994). "Signal transduction and gene regulation: the nuclear response to cAMP". J Biol Chem 269 (26): 17359–17362. PMID 8021233. 
  39. ^ a b Rosen O (1987). "After insulin binds". Science 237 (4821): 1452–1458. doi:10.1126/science.2442814. PMID 2442814. 
  40. ^ Massague J and Gomis RR (2006). "The logic of TGFbeta signaling". FEBS Lett 580 (12): 2811–2820. doi:10.1016/j.febslet.2006.04.033. PMID 16678165. 
  41. ^ Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W (Dec 2005). "Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway". The Biochemical journal 392 (Pt 2): 249–61. doi:10.1042/BJ20050908. PMC 1316260. PMID 16293107. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1316260. 
  42. ^ Vogelstein, B.; Kinzler, K. W. (2004). "Cancer genes and the pathways they control". Nature Medicine 10 (8): 789–799. doi:10.1038/nm1087. PMID 15286780.  edit
  43. ^ a b Alberts B, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1. 

External links

Cell physiology: signal transduction / cell signaling
Signaling pathways
Agents
By location
Other concepts

This entry is from Wikipedia, the leading user-contributed encyclopedia. It may not have been reviewed by professional editors (see full disclaimer)

 
 

 

Copyrights:

McGraw-Hill Science & Technology Dictionary. McGraw-Hill Dictionary of Scientific and Technical Terms. Copyright © 2003, 1994, 1989, 1984, 1978, 1976, 1974 by McGraw-Hill Companies, Inc. All rights reserved.  Read more
McGraw-Hill Science & Technology Encyclopedia. McGraw-Hill Encyclopedia of Science and Technology. Copyright © 2005 by The McGraw-Hill Companies, Inc. All rights reserved.  Read more
$copyright.smallImage.alttext Gale Genetics Encyclopedia. Genetics. Copyright © 2003 by The Gale Group, Inc. All rights reserved.  Read more
 Oxford Dictionary of Biochemistry. Oxford University Press. Oxford Dictionary of Biochemistry and Molecular Biology © 1997, 2000, 2006 All rights reserved.  Read more
Wikipedia on Answers.com. This article is licensed under the Creative Commons Attribution/Share-Alike License. It uses material from the Wikipedia article Signal transduction.  Read more

Related answers
» More
Answer these
» More
Follow us
Facebook Twitter
YouTube

Mentioned in

» More» More

Related topics

» More