Signal transduction
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wikifying
{{Copyedit|date=November 2007}}
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[[Image:Signal transduction v1.png|360px|thumb|right|Overview of signal transduction pathways]]
In [[biology]], '''signal transduction''' refers to any process by which a [[cell (biology)|cell]] converts one kind of [[signal (biology)|signal]] or stimulus into another. Most processes of signal transduction involve ordered sequences of [[biochemistry|biochemical]] [[chemical reaction|reactions]] inside the cell, which are carried out by [[enzyme]]s, activated by [[second messenger]]s, 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 [[Biochemical cascade|cascade]]," beginning with a relatively small stimulus that elicits a large response. This is referred to as ''amplification of the signal''.
==History of the Knowledge==
[[Image:Signal transduction publications graph.jpeg|300px|thumb|right|'''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.<ref name=rensing>{{cite journal | author =Rensing, L. | title = Periodic geophysical and biological signals as Zeitgeber and exogenous inducers in animal organisms | journal = Int. J. Biometeorol. | year=1972 | volume=16 | pages=Suppl:113–125 | pmid = 4621276}}</ref>
Prior to 1977 articles can be found that use the term "signal transmission" or "sensory transduction" within their title or abstract.<ref name=tonndorf>{{cite journal | author =Tonndorf J. | title = Davis-1961 revisited. Signal transmission in the cochlear hair cell-nerve junction | journal = Arch. Otolaryngol. | year=1975 | volume=101 | issue=9 | pages=528–535 | pmid = 169771}}</ref><ref name=ashcroft>{{cite journal | author =Ashcroft SJ, Crossley JR, Crossley PC. | title = The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in the rat | journal = Biochem. J. | year=1976 | volume=154 | issue=3 | pages=701–707 | pmid = 782447}}</ref>
However, it is not until 1977 that papers start to appear with the specific term "signal transduction" within their [[Abstract (summary)|abstract]], and 1979 before this specific term appears within a paper title.<ref name=hildebrand>{{cite journal | author =Hildebrand E. | title = What does Halobacterium tell us about photoreception? | journal = Biophys. Struct. Mech. | year=1977 | volume=3 | issue=1 | pages=69-77 | pmid = 857951 | doi = 10.1007/BF00536457 }}</ref><ref name=kenny>{{cite journal | author =Kenny JJ, Martinez-Maza O. ''et al'' | title = Lipid synthesis: an indicator of antigen-induced signal transduction in antigen-binding cells | journal = J. Immunol. | year=1979 | volume=112 | issue=4 | pages=1278–1284 | pmid = 376714}}</ref>
One source attributes the widespread use of the term signal transduction to a 1980 review article by Rodbell.<ref name= gomperts>{{cite book |last = Gomperts | first = BD. | coauthors = Kramer, IM. Tatham, PER. | title = Signal transduction | publisher = Academic Press | date= 2002 | id=ISBN 0-12-289631-9}}</ref><ref name=rodbell>{{cite journal | author =Rodbell, M. | title = The role of hormone receptors and GTP-regulatory proteins in membrane transduction | journal = Nature | year=1980 | volume=284 | issue=5751 | pages=17–22 | pmid = 6101906 | doi = 10.1038/284017a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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 [[scientific research|research]]{{Fact|date=October 2007}}. 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 [[guanosine triphosphate|GTP]] and [[guanosine triphosphate|GTP-binding proteins]],<ref name=rodbell/> 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 [[review journal|reviews of other papers]]
== Signaling molecules ==
Most signal transduction involves the binding of [[extracellular matrix|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]]. [[Steroid]]s represent another example of extracellular signaling molecules that may cross the [[plasma membrane]] due to their [[lipophilic]] or [[hydrophobic]] nature.<ref name=beato>{{cite journal | author =Beato M, Chavez S and Truss M | title = Transcriptional regulation by steroid hormones | journal = Steroids | year=1996 | volume=61 | issue=4 | pages=240–251 | pmid = 8733009 | doi = 10.1016/0039-128X(96)00030-X <!--Retrieved from CrossRef by DOI bot-->}}</ref> Many, but not all, steroids have receptors within the [[cytoplasm]], and usually act by stimulating the binding of their receptors to the [[promoters|promoter region]] of steroid-responsive [[genes]].<ref name=hammes>{{cite journal | author =Hammes SR | title = The further redefining of steroid-mediated signaling | journal = Proc Natl Acad Sci USA | year=2003 | volume=100 | issue=5 | pages=21680–2170 | pmid = 12606724 | doi = 10.1073/pnas.0530224100 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Within multicellular organisms, there is a diverse number of small molecules and polypeptides that serve to coordinate a cell's individual biological activity within the context of the organism as a whole. These molecules have been functionally classified as:
* [[hormones]] (e.g., [[melatonin]]),<ref name=sugden>{{cite journal | author = Sugden D, Davidson K. ''et al''. | title = Melatonin, melatonin receptors and melanophores: a moving story | journal = Pigment Cell Res. | year=2004 | volume=17 | issue=5 | pages=454–460 | pmid = 15357831 | doi = 10.1111/j.1600-0749.2004.00185.x <!--Retrieved from CrossRef by DOI bot-->}}</ref>
* [[growth factors]] (e.g. [[epidermal growth factor]]),<ref name=carpenter>{{cite journal | author = Carpenter G, and Cohen S. | title = Epidermal growth factor | journal = J. Biol. Chem. | year=1990 | volume=265 | issue=14 | pages=7709–7712 | pmid = 2186024}}</ref>
* [[extracellular matrix|extra-cellular matrix components]] (e.g., [[fibronectin]]),<ref name=ward> Ward M, and Marcey, D. [http://www.callutheran.edu/BioDev/omm/fibro/fibro.htm] Retrieved on [[2007-03-06]]</ref>
* [[cytokines]] (e.g., [[interferon-gamma]]),<ref name=schroder>{{cite journal | author=Schroder ''et al''. | title=Interferon-γ an overview of signals, mechanisms and functions | journal=Journal of Leukocyte Biology | year=2004 | volume=75 | pages=163-189 | url=http://www.jleukbio.org/cgi/content/full/75/2/163 | pmid = 14525967 | doi = 10.1189/jlb.0603252 }}</ref>
* [[chemokines]] (e.g., [[RANTES]]),<ref name=chung>{{cite journal | author =Chung CW, Cooke RM ''et al''. | title = The three-dimensional solution structure of RANTES | journal = Biochemistry | year=1995 | volume=34 | issue=29 | pages=9307–9314 | pmid = 7542919 | doi = 10.1021/bi00029a005 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
* [[neurotransmitters]] (e.g., [[acetylcholine]]),<ref name=kistler>{{cite journal | author =Kistler J, Stroud RM ''et al''. | title = Structure and function of an acetylcholine receptor | journal = Biophys. J. | year=1982 | volume=37 | issue=1 | pages=371–383 | pmid = 7055628}}</ref> and
* [[neurotrophins]] (e.g., [[nerve growth factor]]).<ref name=wiesmann>{{cite journal | author =Wiesmann, C. and de Vos, AM. | title = Nerve growth factor: structure and function | journal = Cell Mol Life Sci | year=2001 | volume=58 | issue=5-6 | pages=748–759 | pmid = 11437236 | doi = 10.1007/PL00000898 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
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]]<ref name=goldstein>{{cite journal | author =Goldstein, A. | title = Opioid peptides endorphins in pituitary and brain | journal = Science | year=1976 | volume=193 | issue=4258 | pages=1081–1086 | pmid = 959823 | doi = 10.1126/science.959823 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
and small molecules such as [[serotonin]]<ref name=kroeze>{{cite journal | author =Kroeze WK, Kristiansen K, and Roth BL. | title = Molecular biology of serotonin receptors, structure and function at the molecular level | journal = Curr Top Med Chem | year=2002 | volume=2 | issue=6 | pages=507–528 | pmid = 12052191 | doi = 10.2174/1568026023393796 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
and [[dopamine]].<ref name=missale>{{cite journal | author =Missale C, Nash SR. ''et al'' | title = Dopamine receptors:from structure to function | journal = Physiol. Rev. | year=1998 | volume=78 | issue=1 | pages=189–225 | pmid = 9457173}}</ref> Hormones are also a generic class of molecule able to initiate signal transduction, these include [[insulin]] (a polypeptide),<ref name=adams>{{cite journal | author =Adams TE, Epa, VC ''et al'' | title = Structure and function of the type 1 insulin-like growth factor receptor | journal = Cell Mol Life Sci | year=2000 | volume=57 | issue=7 | pages=1050–1093 | pmid = 10961344 | doi = 10.1007/PL00000744 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
[[testosterone]] (a [[steroid]]),<ref name= roy>{{cite journal | author =Roy AK and Chatterjee B. | title = Androgen action | journal = Crit Rev Eukaryot Gene Expr. | year=1995 | volume=5 | issue=2 | pages=157–176 | pmid = 8845582}}</ref>
and [[epinephrine]] (an [[amino acid]] derivative, in essence a small [[Organic chemistry|organic]] molecule).<ref name=small>{{cite journal | author =Small KM, McGraw DW and Liggett SB. | title = Pharmacology and physiology of human adrenergic receptor polymorphisms | journal = Annu Rev Pharmacol Toxicol | year=2003 | volume=43 | pages=381–411 | pmid = 12540746 | doi = 10.1146/annurev.pharmtox.43.100901.135823 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
The classification of one molecule into one class of another is not exact. For example, [[epinephrine]] and [[norepinephrine]] secreted by the [[central nervous system]] act as neurotransmitters. However, [[epinephrine]] when secreted by the [[adrenal medulla]] acts as a [[hormone]].
== Environmental stimuli ==
In [[bacterium|bacteria]] and other single-cell [[organism]]s, the variety of a signal transduction processes of which the cell is capable influences how many ways it can react and respond to its environment. In [[multicellular organisms]], a multitude of different signal transduction processes are required for coordinating the behavior of individual cells to support the function of the organism as a whole. As may be expected, the more complex the organism, the more complex the repertoire of signal transduction processes the organism must possess. Thus, [[sense|sensing]] of both the external and internal environments at the cellular level relies on signal transduction. Many disease processes such as [[diabetes]], [[atherosclerosis|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,<ref name=burns>{{cite journal | author =Burns ME and Arshavsky VY. | title = Beyond counting photons: trials and trends in vertebrate visual transduction | journal = Neuron | year=2005 | volume=48 | issue=3 | pages=387–401 | pmid = 16269358 | doi = 10.1016/j.neuron.2005.10.014 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
[[odorant]]s binding to [[olfactory receptor neuron|odorant receptors]] in the [[olfactory epithelium|nasal epithelium]],<ref name=ronnett>{{cite journal | author =Ronnett GV and Moon C. | title = G proteins and olfactory signal transduction | journal = Annu Rev Physiol | year=2002 | volume=64 | pages=189–222 | pmid = 11826268 | doi = 10.1146/annurev.physiol.64.082701.102219 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
and bitter and sweet tastes stimulating [[G protein-coupled receptor|taste receptors]] in the [[taste buds]].<ref name=wong>{{cite journal | author =Wong GT, Gannon KS and Margolskee RF. | title = Transduction of bitter and sweet taste by gustducin | journal = Nature | year=1996 | volume=381 | issue=6585 | pages=796–800 | pmid = 8657284 | doi = 10.1038/381796a0 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
Certain microbial molecules, e.g., viral [[nucleotide]]s, bacterial [[lipopolysaccharide]]s, and protein [[antigen]]s, are able to elicit an [[immune system]] response against invading [[pathogen]]s, 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, [[Dictyostelid|slime molds]] secrete [[cyclic adenosine monophosphate|cyclic-AMP]] upon starvation, which stimulates individual cells in the immediate environment to aggregate.<ref name=hanna>{{cite journal | author =Hanna MH, Nowicki JJ and Fatone MA | title = 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 | journal = J Bacteriol | year=1984 | volume=157 | issue=2 | pages=345–349 | pmid = 215252}}</ref>
[[Yeast]] also use [[Mating of yeast|mating factor]]s to determine the mating types of other yeast and participate in sexual reproduction.<ref name=sprague>{{cite journal | author = Sprague GF Jr.| title = Signal transduction in yeast mating: receptors, transcription factors, and the kinase connection | journal = Trends Genet | year=1991 | volume=7 | issue=11-12 | pages=393–398 | pmid = 1668192}}</ref>
== Cellular responses ==
[[Transcription (genetics)|Activation]] of [[gene]]s,<ref name=lalli>{{cite journal | author =Lalli E and Sassone-Corsi P | title = Signal transduction and gene regulation: the nuclear response to cAMP | journal = j Biol Chem | year=1994 | volume=269 | issue=26 | pages=17359–17362 | pmid = 8021233}}</ref>
alterations in [[metabolism]],<ref name=rosen>{{cite journal | author =Rosen O | title = After insulin binds | journal = Science | year=1987 | volume=237 | issue=4821 | pages=1452–1458 | pmid = 2442814 | doi = 10.1126/science.2442814 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
the continued [[cell division|proliferation]] and [[apoptosis|death]] of the cell,<ref name=guo>{{cite journal | author = Guo D, Jia Q. ''et al'' | title = Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation | journal = J Biol Chem | year=1995 | volume=270 | issue=12 | pages=6729-6733 | pmid = 7896817 | doi = 10.1074/jbc.270.12.6729 }}</ref>
and the stimulation or suppression of [[chemotaxis|locomotion]],<ref name=bornfeldt>{{cite journal | author =Bornfeldt KE, Raines EW. ''et al''. | title = Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation. | journal = Ann N Y Acad Sci | year=1995 | volume=766 | pages=416-430 | pmid = 7486687 | doi = 10.1111/j.1749-6632.1995.tb26691.x }}</ref>
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 factor]]s 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]]<ref name=rosen/> 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]]''.<ref name=massaque>{{cite journal | author =Massague J and Gomis RR | title = The logic of TGFbeta signaling | journal = FEBS Lett | year=2006 | volume=580 | issue=12 | pages=2811–2820 | pmid = 16678165 | doi = 10.1016/j.febslet.2006.04.033 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
[[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.<ref name=kistler/> This results in an altering of the cell's [[membrane potential]] and is important for processes such as the neural conduction of [[Neuron#Adaptations to carry action potentials|electrochemical impulses]]. Ligands can be [[epidermal growth factor|freely soluble]],<ref name=carpenter/> or can be found on the surface of other cells or within the [[extracellular matrix]].<ref name=ward/> Such cell surface or extracellular matrix ligands signal between cells when they come in contact with each other, such as when a [[Dendritic Cell|phagocytic cell]] presents [[antigen]]s to [[T cell receptor|lymphocytes]], or upon adhesion to the extracellular matrix, as when [[integrins]] at the cell surface of [[fibroblasts]] engage [[fibronectin]].<ref name=johansson>{{cite journal | author = Johansson S. Svineng G ''et al''. | title = Fibronectin-integrin interactions | journal = Front. Biosci | year=1997 | volume=2 | pages=d126–146 | pmid = 9159220}}</ref>
Most mammalian cells require stimulation to control not only cell division but also survival. In the absence of [[growth factor]] stimulation, [[apoptosis|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:
#[[Intracellular]] receptors and
#[[Cell-surface]] receptors.
[[ligand-gated ion channel|Ligand-gated ion channel receptors]] are a class of receptor that may occur both at the cell-surface or [[intracellular]]ly.
Receptors that are solely [[intracellular]] include those for [[steroid hormone]]s, [[thyroid hormone]], [[retinoic acid]], and derivatives of [[vitamin D|vitamin D<sub>3</sub>]]. 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 [[signal transduction#intracellular receptors|intracellular receptors]] section below for more details.
===Cell-surface receptors===
{{Unreferencedsection|date=November 2007}}
Cell-surface receptors are [[transmembrane protein|integral transmembrane protein]]s and recognize the vast majority of extracellular signaling molecules. [[Transmembrane receptor]]s 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 (biochemistry)|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 (biochemistry)|ligand]]. Upon binding, the ligand initiates the transmission of a signal across the plasma membrane by inducing a change in the shape or [[Chemical conformation|conformation]] of the intracellular part of the receptor (see this link [http://www.bio-balance.com/JMGM_article.pdf]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 [[Eukaryote|eukaryotic]] cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity. These enzymes include [[tyrosine kinase]], heterotrimeric [[G protein]]s, [[small GTPase]]s, various serine/threoine [[protein kinase]]s, [[protein phosphatase|phosphatase]]s, [[Phosphoinositide 3-kinase|lipid kinases]], and [[phospholipase C|hydrolases]]. Some receptor-stimulated enzymes create specific [[second messenger]]s including [[cyclic nucleotide]]s, such as [[cyclic AMP]] (cAMP) and [[cyclic GMP]] (cGMP), [[Phosphatidylinositol]] derivatives, such as [[PIP3|Phosphatidylinositol-triphosphate]] (PIP<sub>3</sub>), [[diglyceride|Diacylglycerol]] (DAG) and [[IP3|Inositol-triphosphate]] (IP<sub>3</sub>), [[IP3|IP<sub>3</sub>]], controlling the release of intracellular calcium stores into the cytoplasm (see [[signal transduction#second messengers|second messengers]] section later in this article). Other activated proteins interact with [[adapter protein]]s. 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 [[structural domain|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]]. PIP<sub>3</sub>, PIP<sub>2</sub> and other phosphoinositides may bind to the [[Pleckstrin homology domain]]s 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:
#[[G-protein coupled receptors]], e.g., [[Chemokine]] receptors
#[[Receptor tyrosine kinase]]s, e.g., [[Growth factor]] receptors,
#[[Integrins]]
#[[Toll-like receptor]]s
Further examples are given in the [[transmembrane receptor]] article.
==== G-protein-coupled receptors ====
{{details|G-protein-coupled receptor}}
[[Image:G protein signal transduction (epinephrin pathway).png|300px|thumb|right|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 protein]]s 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 receptor]]s, neurotransmitter receptors, [[olfactory receptor]]s, [[opioid receptor]]s, [[chemokine receptor]]s, 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.<ref>{{cite book |author=Jeremy M. Berg, John L. Tymoczko, Lubert Stryer; Web content by Neil D. Clarke |title=Biochemistry |publisher=W.H. Freeman |location=San Francisco |year=2002 |pages= |isbn=0-7167-4954-8 |oclc= |doi=}}</ref> The activated G protein subunits detach from the receptor and initiate signaling from many ''downstream'' effector proteins, including [[phosphodiesterase]]s and [[adenylyl cyclase]]s, [[phospholipase]]s, and [[ion channels]] that permit the release of second messenger molecules such as [[Cyclic adenosine monophosphate|cyclic-AMP]] (cAMP), [[Cyclic guanosine monophosphate|cyclic-GMP]] (cGMP), [[inositol triphosphate]] (IP3), diacylglycerol (DAG), and [[calcium (second messenger)|calcium (Ca<sup>2+</sup>) ions]].<ref>{{cite journal |author = Yang W, Xia S |title=Mechanisms of regulation and function of G-protein-coupled receptor kinases |journal=World J Gastroenterol |volume=12 |issue=48 |pages=7753-7 |year=2006 |pmid=17203515}}</ref> 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 [[transfection|transfected]] with the CXCR2 [[mutant]] underwent a [[malignant transformation]].<ref name=burger>{{cite journal |author=Burger M, Burger, JA ''et al'' |title=Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor | journal=J. Immunol. | volume=163 |issue=4 |pages=2017–2022 |year=1999 | pmid= 10438939}}</ref> The result of the [[point mutation]] was the [[gene expression|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 kinase]]s (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|insulin receptor]] and the [[Insulin-like growth factor-1 receptor|insulin-like growth factor receptor]]s, and many others receptors.<ref name=LiHris>{{cite journal |author=Li E, Hristova K |title=Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies |journal=Biochemistry |volume=45 |issue=20 |pages=6241-51 |year=2006 |pmid=16700535 | doi = 10.1021/bi060609y }}</ref> To conduct their biochemical signals, RTKs need to form [[dimer]]s in the [[plasma membrane]]<ref name=Schlessinger1988>{{cite journal
| author = Schlessinger, J.
| year = 1988
| title = Signal transduction by allosteric receptor oligomerization.
| journal = Trends Biochem Sci
| volume = 13
| issue = 11
| pages = 443-7
| url = http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=3075366&cmd=showdetailview&indexed=google
| accessdate = 2007-11-24
| doi = 10.1016/0968-0004(88)90219-8 <!--Retrieved from CrossRef by DOI bot-->
| pmid = 3075366 }}</ref>. 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 [[tyrosine]]s 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, [[cell differentiation|differentiation]], [[metabolism]], and [[cell migration|migration]].<ref name=LiHris/>
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 [[Ral]] families, referred to collectively as [[small G protein]]s. 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 Factor]]s, 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 [[gene expression|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]].<ref name=roskoski>{{cite journal |author=Roskoski, R, Jr. | title=The ErbB/HER receptor protein-tyrosine kinases and cancer |journal= Biochem. Biophys. Res. Commun.| volume=319 | issue=1 |pages=1–11 |year=2004 | pmid=15158434 | doi = 10.1016/j.bbrc.2004.04.150 <!--Retrieved from CrossRef by DOI bot-->}}</ref>
==== Integrins ====
{{details|Integrin}}
[[Image:Integrin sig trans overview.jpeg|300px|thumb|right|An overview of integrin-mediated signal transduction, adapted from Hehlgens ''et al'' (2007).<ref name=hehlgans>{{cite journal | author=Hehlgans, S. Haase, M. and Cordes, N. | title=Signaling via integrins: Implications for cell survival and anticancer strategies | journal=Biochim. Biophys. Acta. | volume=1775 | issue=1| pages=163–180 |year=2007 |pmid=17084981}}</ref>]]
Integrins are produced by a wide variety of [[cell type]]s, 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]], [[parvin]]s, [[p130Cas]], [[Src-family kinase]]s, and [[GTPase]]s of the [[Rho]] family, the main protein coordinating signal transduction being [[integrin-linked kinase|ILK]].<ref name=hehlgans/> 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 cell]]s. 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 [[inflammation|inflamatory 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.<ref name=gilcrease>{{cite journal | author=Gilcrease MZ. | title=Integrin signaling in epithelial cells | journal=Cancer Lett. | volume=247| issue=1 | pages=1-25 |year=2006 | pmid=16725254 | doi = 10.1016/j.canlet.2006.03.031 }}</ref>
==== Toll-like receptors ====
{{details|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|Tirap]] (also called Mal), [[Trif]], and Tram.<ref name=Yamamoto_2003a>{{cite journal | doi = 10.1016/j.canlet.2006.03.031 |author=Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S |title=Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway |journal=Science |volume=301 |issue=5633 |pages=640–3 |year=2003 |pmid=12855817}}</ref><ref name=Yamamoto_2003b>{{cite journal | doi = 10.1016/j.canlet.2006.03.031 |author=Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S |title=TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway |journal=Nat Immunol |volume=4 |issue=11 |pages=1144–50 |year=2003 |pmid=14556004}}</ref><ref name=Yamamoto_2002>{{cite journal | doi = 10.1016/j.canlet.2006.03.031 | author=Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S |title=Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4 |journal=Nature |volume=420 |issue=6913 |pages=324–9 |year=2002 |pmid=12447441}}</ref> 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====
{{details|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 [[Electric charge|electrical charge]] across the membrane. In [[neuron]]s, this mechanism underlies the [[action potential]]s that travel along [[nerve]]s. 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 ===
{{see|Intracellular receptor}}
Intracellular receptors include [[nuclear receptor]]s and [[cytoplasmic receptor]]s, 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 (genetics)|transcription]] activators; on binding with the ligand (the hormone), the ligands will pass through the [[nuclear membrane]] into the [[cell nucleus|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-<font color=cyan>AAAA</font>BBBB<font color=green>CCCC</font><font color=brown>DDDD</font><font color=magenta>EEEE</font><font color = Yellow>FFFF</font>-C
where <font color=green>CCCC</font> is the DNA-binding domain that contains [[zinc finger]]s, and <font color=magenta>EEEE</font> 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 receptor]]s''' 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 protein]]s (also known as ''[[heatshock protein]]s'' or ''Hsp''s). The ''Hsp''s are necessary to activate the receptor by assisting the protein to [[protein folding|fold]] in a way such that the [[signal sequence]] that enables its passage into the nucleus is accessible.<br>
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 (biology)|crosstalk]]''.
'''[[Retinoic acid receptor|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 [[Protein precursor|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 [[Pattern recognition receptor|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 [[caspase]]s (e.g., [[caspase 1]]) and initiate processing of particular [[cytokine]]s (e.g., [[interleukin-1]]β).<ref>{{cite journal |author=Delbridge L, O'Riordan M |title=Innate recognition of intracellular bacteria |journal=Curr Opin Immunol |volume=19 |issue=1 |pages=10–6 |year=2007 |pmid=17126540 | doi = 10.1016/j.coi.2006.11.005 <!--Retrieved from CrossRef by DOI bot-->}}</ref> 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.<ref>{{cite journal |author=Fujita T, Onoguchi K, Onomoto K, Hirai R, Yoneyama M |title=Triggering antiviral response by RIG-I-related RNA helicases |journal=Biochimie |volume= |issue= |pages= |year= |pmid=17379377 | doi = 10.1016/j.canlet.2006.03.031 }}</ref>
== Second messengers ==
Intracellular signal transduction is largely carried out by [[second messenger]] molecules.
'''Ca<small><sup>2+</sup></small>''' concentration is usually maintained at a very low level in the cytosol by sequestration in the smooth endoplasmic reticulum and the mitochondria. Ca<small><sup>2+</sup></small> release from the endoplasmic reticulum into the [[cytosol]] results in the binding of the released Ca<small><sup>2+</sup></small> to signaling proteins that are then activated. There are two combined receptor/ion channel proteins that perform the task of controlled transport of Ca<small><sup>2+</sup></small>:
* The ''InsP<sub><small>3</small></sub>-receptor'' will transport Ca<small><sup>2+</sup></small> 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 InsP<sub><small>3</small></sub> receptor and stimulated to transport Ca<small><sup>2+</sup></small> into the cytosol by ''recognizing Ca<small><sup>2+</sup></small> on its cytosolic side'', thus establishing a [[feedback mechanism]]; a small amount of Ca<small><sup>2+</sup></small> in the cytosol near the receptor will cause it to release even more Ca<small><sup>2+</sup></small>. It is especially important in [[neuron]]s and [[muscle cell]]s. In [[heart]] and [[pancreas]] cells, another second messenger ([[cyclic-ADP ribose]]) takes part in the receptor activation. The localized and time-limited activity of Ca<small><sup>2+</sup></small> in the cytosol is also called a ''Ca<small><sup>2+</sup></small> wave''. Once released into the cytosol from intracellular stores or extracellular sources, Ca<small><sup>2+</sup></small> acts as a signal molecule within the cell. This works by tightly limiting the time and space when Ca<small><sup>2+</sup></small> is free (and thus active). Therefore, the concentration of free Ca<small><sup>2+</sup></small> within the cell is usually very low; it is stored within [[organelle]]s, usually the [[endoplasmic reticulum]] ([[sarcoplasmic reticulum]] in muscle cells), where it is bound to molecules like [[calreticulin]].
Ca<small><sup>2+</sup></small> is used in a multitude of processes, among them [[muscle]] contraction, release of neurotransmitter from nerve endings, [[visual perception|vision]] in [[retina]] cells, [[cell proliferation|proliferation]], [[secretion]], [[cytoskeleton]] management, [[cell migration]], [[gene expression]], and [[metabolism]]. The three main pathways that lead to Ca<small><sup>2+</sup></small> activation are :
# [[G protein]]-regulated pathways
# Pathways regulated by receptor-[[tyrosine kinase]]s
# Ligand- or current-regulated [[ion channel]]s
There are two different ways by which Ca<small><sup>2+</sup></small> can regulate proteins:
# A direct recognition of Ca<small><sup>2+</sup></small> by the protein
# Binding of Ca<small><sup>2+</sup></small> in the [[active site]] of an [[enzyme]].
One of the best-studied interactions of Ca<small><sup>2+</sup></small> with a protein is the regulation of [[calmodulin]] by Ca<small><sup>2+</sup></small>. Calmodulin itself can regulate other proteins, or be part of a larger protein (for example, [[phosphorylase kinase]]). The Ca<small><sup>2+</sup></small>/calmodulin complex plays an important role in proliferation, [[mitosis]], and neural signal transduction.
'''Lipophilic second messenger molecules''' - These molecules are all derived from lipids that normally reside in cellular membranes. Enzymes stimulated by activated receptors modify these lipids, converting them into second messengers. One example of [[lipophilic]] second messenger molecule is [[diglyceride|diacylglycerol]], required for the activation of [[protein kinase C]]. Others are [[ceramide]], the [[eicosanoid]]s, and [[lysophosphatidic acid]].
'''Nitric oxide (NO) as second messenger''' - The gas [[nitric oxide]] 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 cofactors. Some of these modifications are reversible and work through a [[redox]] mechanism. In high concentrations, NO is toxic, and is thought to be responsible for some damage after a [[stroke]]. NO serves multiple functions. These include:
# Relaxation of [[blood vessel]]s
# Regulation of [[exocytosis]] of [[neurotransmitter]]s
# Cellular [[immune system|immune response]]
# Modulation of the [[Baldness|Hair Cycle]]
# Production and maintenance of penile [[erection]]s
# Activation of apoptosis by initiating signals that lead to H2AX phosphorylation.
== See also ==
* [[Functional selectivity]]
* [[G protein-coupled receptor]] -- [[GTPase]]s -- [[Protein phosphatase]]
* [[MAPK/ERK pathway]] - a signal transduction pathway linking cell surface receptors to transcription factors
* [[Redox signaling]]
==References==
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{{Reflist|2}}
== Further reading ==
; Non-technical
* [http://bactra.org/notebooks/signal-transduction.html Cosma Shalizi's "Signal transduction" Notebook from 2003-01-20 used under the GFDL with permission]
* Werner R. Loewenstein, ''The Touchstone of Life: Molecular Information, Cell Communication, and the Foundations of Life'', Oxford University Press, [[1999]], ISBN 0-19-514057-5
; Technical
* Gomperts, Kramer, Tatham, "Signal Transduction", AP/Elsevier [2002], ISBN 0122896319. Reference book, for more information: http://www.cellbiol.net .
* Gerhard Krauss, ''Biochemistry of Signal Transduction and Regulation'', Wiley-VCH, [[1999]], ISBN 3-527-30378-2
* John T. Hancock, ''Cell Signalling'', Addison-Wesley, [[1998]] ISBN 0-582-31267-1
== External links ==
* [http://www.biochemweb.org/signaling.shtml Signal Transduction - The Virtual Library of Biochemistry and Cell Biology]
* [http://www.gene-regulation.com/cgi-bin/pub/databases/transpath/search.cgi TRANSPATH(R)] - A database about signal transduction pathways
* [http://stke.sciencemag.org/ ''Science'''s STKE - Signal Transduction Knowledge Environment], from the journal ''Science'', published by AAAS.
* {{MeshName|Signal+Transduction}}
* [http://www.signaling-gateway.org/ UCSD-Nature Signaling Gateway], from Nature Publishing Group
* [http://www.litinspector.org LitInspector] - Signal transduction pathway mining in PubMed abstracts
{{Cell_signaling}}
{{Signal transduction}}
[[Category:Cell biology]]
[[Category:Signal transduction]]
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[[Category:Neurochemistry]]
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