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Your current IP address is 8.222.208.146. </p> <div class="paragraphbreak" style="margin-top:0.5em"></div><div style="font-size: 16px;"> <p>Even while globally blocked, you will <i>usually</i> still be able to edit pages on <a href="https://meta.wikimedia.org/wiki/" class="extiw" title="m:">Meta-Wiki</a>. </p> </div> <div class="paragraphbreak" style="margin-top:0.5em"></div><div style="font-size: 16px;"> <p>If you believe you were blocked by mistake, you can find additional information and instructions in the <a href="https://meta.wikimedia.org/wiki/Special:MyLanguage/No_open_proxies" class="extiw" title="m:Special:MyLanguage/No open proxies">No open proxies</a> global policy. Otherwise, to discuss the block please <a href="https://meta.wikimedia.org/wiki/Steward_requests/Global" class="extiw" title="m:Steward requests/Global">post a request for review on Meta-Wiki</a>. You could also send an email to the <a href="https://meta.wikimedia.org/wiki/Special:MyLanguage/Stewards" class="extiw" title="m:Special:MyLanguage/Stewards">stewards</a> <a href="https://meta.wikimedia.org/wiki/Special:MyLanguage/VRT" class="extiw" title="m:Special:MyLanguage/VRT">VRT</a> queue at <kbd>stewards@wikimedia.org</kbd> including all above details. </p> </div> <p>Other useful links: <a href="https://meta.wikimedia.org/wiki/Global_blocks" class="extiw" title="m:Global blocks">Global blocks</a> · <a href="/wiki/Help:I_have_been_blocked" title="Help:I have been blocked">Help:I have been blocked</a> </p> </div></li></ul><hr /> <div id="viewsourcetext">You can view and copy the source of this page:</div><textarea readonly="" accesskey="," id="wpTextbox1" cols="80" rows="25" style="" class="mw-editfont-monospace" lang="en" dir="ltr" name="wpTextbox1">{{Short description|Cascade of intracellular and molecular events for transmission/amplification of signals}} {{About|signaling at the cellular level|systemic signal transduction|Transduction (physiology)}}'''Signal transduction''' is the process by which a chemical or physical signal is transmitted through a cell as a [[biochemical cascade|series of molecular events]]. Proteins responsible for detecting stimuli are generally termed [[receptor (biology)|receptors]], although in some cases the term sensor is used.<ref>{{cite book |editor1-last=Bradshaw |editor1-first=Ralph A. |editor2-last=Dennis |editor2-first=Edward A. | name-list-style = vanc |title=Handbook of Cell Signaling|date=2010|publisher=Academic Press|location=Amsterdam, Netherlands|isbn=9780123741455|edition=2nd}}</ref> The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a [[biochemical cascade]], which is a chain of biochemical events known as a [[Cell signaling#Signaling pathways|signaling pathway]]. When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events.<ref>{{cite journal | vauthors = Papin JA, Hunter T, Palsson BO, Subramaniam S | title = Reconstruction of cellular signalling networks and analysis of their properties | journal = Nature Reviews. Molecular Cell Biology | volume = 6 | issue = 2 | pages = 99–111 | date = February 2005 | pmid = 15654321 | doi = 10.1038/nrm1570 | s2cid = 3065483 }}</ref> At the molecular level, such responses include changes in the [[transcription (biology)|transcription]] or [[translation (biology)|translation]] of genes, and [[post-translational modification|post-translational]] and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controlling [[cell growth]], proliferation, [[metabolism]] and many other processes.<ref>{{cite book |last=Krauss |first=Gerhard | name-list-style = vanc |date=2008 |url=https://archive.org/details/biochemistryofsi00krau/page/15/mode/2up|title=Biochemistry of Signal Transduction and Regulation |publisher=Wiley-VCH |pages=15 |isbn=978-3527313976 }}</ref> In multicellular organisms, signal transduction pathways regulate [[Cellular communication (biology)|cell communication]] in a wide variety of ways. Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. [[Ligand (biochemistry)|Ligands]] are termed ''first messengers'', while receptors are the ''signal transducers'', which then activate ''primary effectors''. Such effectors are typically proteins and are often linked to [[second messenger]]s, which can activate ''secondary effectors'', and so on. Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signaling molecule can generate a response involving hundreds to millions of molecules.<ref name="Campbell">{{cite book | last1 = Reece | first1 = Jane | last2 = Campbell | first2 = Neil | name-list-style = vanc |title=Biology |publisher=Benjamin Cummings |location=San Francisco |year=2002 |isbn=978-0-8053-6624-2 | url=https://archive.org/details/biologyc00camp }}</ref> As with other signals, the transduction of biological signals is characterised by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological.<ref>{{cite journal | vauthors = Kolch W, Halasz M, Granovskaya M, Kholodenko BN | title = The dynamic control of signal transduction networks in cancer cells | journal = Nature Reviews. Cancer | volume = 15 | issue = 9 | pages = 515–27 | date = September 2015 | pmid = 26289315 | doi = 10.1038/nrc3983 | s2cid = 35252401 }}</ref> With the advent of [[computational biology]], the [[systems biology|analysis]] of signaling pathways and networks has become an essential tool to understand cellular functions and [[disease]], including signaling rewiring mechanisms underlying responses to acquired drug resistance.<ref>Bago R, Sommer E, Castel P, Crafter C, Bailey FP, Shpiro N, Baselga J, Cross D, Eyers PA, Alessi DR (2016) The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. EMBO Journal 35:1902-22</ref>[[File:Signal transduction pathways.svg|thumb|481x481px|Simplified representation of major signal transduction pathways in mammals.]] ==Stimuli== {{Main|Stimulus (physiology)}} [[File:Signal Transduction.jpg|thumb|276x276px|3D Medical animation still showing signal transduction.]] The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of [[epidermal growth factor|EGF]], to intracellular events, such as the DNA damage resulting from [[replicative senescence|replicative]] [[telomere]] attrition.<ref>{{cite journal | vauthors = Smogorzewska A, de Lange T | title = Different telomere damage signaling pathways in human and mouse cells | journal = The EMBO Journal | volume = 21 | issue = 16 | pages = 4338–48 | date = August 2002 | pmid = 12169636 | pmc = 126171 | doi = 10.1093/emboj/cdf433 }}</ref> Traditionally, signals that reach the central nervous system are classified as [[sense]]s. These are transmitted from [[neuron]] to neuron in a process called [[synaptic transmission]]. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.<ref>{{cite journal | vauthors = Lawrence PA, Levine M | title = Mosaic and regulative development: two faces of one coin | journal = Current Biology | volume = 16 | issue = 7 | pages = R236-9 | date = April 2006 | pmid = 16581495 | doi = 10.1016/j.cub.2006.03.016 | doi-access = free }}</ref> ===Ligands=== {{Main|Ligand (biochemistry)}} The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as ''receptor activation''. Most ligands are soluble molecules from the extracellular medium which bind to [[cell surface receptors]]. These include [[growth factors]], [[cytokines]] and [[neurotransmitters]]. Components of the [[extracellular matrix]] such as [[fibronectin]] and [[hyaluronan]] can also bind to such receptors ([[integrins]] and [[CD44]], respectively). In addition, some molecules such as [[steroid hormones]] are lipid-soluble and thus cross the plasma membrane to reach cytoplasmic or [[nuclear receptors]].<ref name=beato>{{cite journal | vauthors = Beato M, Chávez S, Truss M | title = Transcriptional regulation by steroid hormones | journal = Steroids | volume = 61 | issue = 4 | pages = 240–51 | date = April 1996 | pmid = 8733009 | doi = 10.1016/0039-128X(96)00030-X | s2cid = 20654561 }}</ref> In the case of [[steroid hormone receptor]]s, their stimulation leads to binding to the [[promoter (biology)|promoter region]] of steroid-responsive genes.<ref name=hammes>{{cite journal | vauthors = Hammes SR | title = The further redefining of steroid-mediated signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 5 | pages = 2168–70 | date = March 2003 | pmid = 12606724 | pmc = 151311 | doi = 10.1073/pnas.0530224100 | bibcode = 2003PNAS..100.2168H | doi-access = free }}</ref> Not all classifications of signaling molecules take into account the molecular nature of each class member. For example, [[odorants]] belong to a wide range of molecular classes,<ref name=ronnett>{{cite journal | vauthors = Ronnett GV, Moon C | title = G proteins and olfactory signal transduction | journal = Annual Review of Physiology | volume = 64 | issue = 1 | pages = 189–222 | year = 2002 | pmid = 11826268 | doi = 10.1146/annurev.physiol.64.082701.102219 }}</ref> as do neurotransmitters, which range in size from small molecules such as [[dopamine]]<ref name=missale>{{cite journal | vauthors = Missale C, Nash SR, Robinson SW, Jaber M, Caron MG | title = Dopamine receptors: from structure to function | journal = Physiological Reviews | volume = 78 | issue = 1 | pages = 189–225 | date = January 1998 | pmid = 9457173 | doi = 10.1152/physrev.1998.78.1.189 }}</ref> to [[neuropeptides]] such as [[endorphins]].<ref name=goldstein>{{cite journal | vauthors = Goldstein A | title = Opioid peptides endorphins in pituitary and brain | journal = Science | volume = 193 | issue = 4258 | pages = 1081–6 | date = September 1976 | pmid = 959823 | doi = 10.1126/science.959823 | bibcode = 1976Sci...193.1081G }}</ref> Moreover, some molecules may fit into more than one class, e.g. [[epinephrine]] is a neurotransmitter when secreted by the [[central nervous system]] and a hormone when secreted by the [[adrenal medulla]]. Some receptors such as [[HER2]] are capable of '''ligand-independent activation''' when overexpressed or mutated. This leads to constitutive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other [[ErbB|EGFR]]s, constitutive activation leads to hyperproliferation and [[cancer]].<ref>{{cite journal | vauthors = Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, etal | title = Comprehensive molecular portraits of human breast tumours | journal = Nature | volume = 490 | issue = 7418 | pages = 61–70 | date = October 2012 | pmid = 23000897 | pmc = 3465532 | doi = 10.1038/nature11412 | bibcode = 2012Natur.490...61T | collaboration = The Cancer Genome Atlas Network }}</ref> ===Mechanical forces=== {{Main|Mechanotransduction}} The prevalence of [[basement membranes]] in the tissues of [[Eumetazoa]]ns means that most cell types require [[cell adhesion|attachment]] to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum. Such signaling is mainly orchestrated in [[focal adhesions]], regions where the [[integrin]]-bound [[actin]] [[cytoskeleton]] detects changes and transmits them downstream through [[YAP1]].<ref>{{cite journal | vauthors = Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N, Piccolo S | display-authors = 6 | title = Role of YAP/TAZ in mechanotransduction | journal = Nature | volume = 474 | issue = 7350 | pages = 179–83 | date = June 2011 | pmid = 21654799 | doi = 10.1038/nature10137 | s2cid = 205225137 }}</ref> Calcium-dependent [[cell adhesion molecules]] such as [[cadherin]]s and [[selectin]]s can also mediate mechanotransduction.<ref>{{cite journal | vauthors = Ingber DE | title = Cellular mechanotransduction: putting all the pieces together again | journal = FASEB Journal | volume = 20 | issue = 7 | pages = 811–27 | date = May 2006 | pmid = 16675838 | doi = 10.1096/fj.05-5424rev | doi-access = free | s2cid = 21267494 }}</ref> Specialised forms of mechanotransduction within the nervous system are responsible for [[mechanosensation]]: [[hearing]], [[touch]], [[proprioception]] and [[sense of balance|balance]].<ref>{{cite journal | vauthors = Kung C | title = A possible unifying principle for mechanosensation | journal = Nature | volume = 436 | issue = 7051 | pages = 647–54 | date = August 2005 | pmid = 16079835 | doi = 10.1038/nature03896 | bibcode = 2005Natur.436..647K | s2cid = 4374012 }}</ref> ===Osmolarity=== {{Main|Osmoreceptor}} Cellular and systemic control of [[osmotic pressure]] (the difference in [[osmolarity]] between the [[cytosol]] and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction).<ref name="Pedersen">{{cite journal | vauthors = Pedersen SF, Kapus A, Hoffmann EK | title = Osmosensory mechanisms in cellular and systemic volume regulation | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 9 | pages = 1587–97 | date = September 2011 | pmid = 21852585 | doi = 10.1681/ASN.2010121284 | doi-access = free }}</ref> These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors are [[transient receptor potential channel]]s present in the [[primary cilium]] of human cells.<ref name="Pedersen" /><ref>{{cite journal | vauthors = Verbalis JG | title = How does the brain sense osmolality? | journal = Journal of the American Society of Nephrology | volume = 18 | issue = 12 | pages = 3056–9 | date = December 2007 | pmid = 18003769 | doi = 10.1681/ASN.2007070825 | doi-access = free }}</ref> In yeast, the HOG pathway has been extensively characterised.<ref>{{cite journal | vauthors = Hohmann S | title = Osmotic stress signaling and osmoadaptation in yeasts | journal = Microbiology and Molecular Biology Reviews | volume = 66 | issue = 2 | pages = 300–72 | date = June 2002 | pmid = 12040128 | pmc = 120784 | doi = 10.1128/MMBR.66.2.300-372.2002 }}</ref> ===Temperature=== {{Main|Thermoception}} The sensing of temperature in cells is known as thermoception and is primarily mediated by [[transient receptor potential channel]]s.<ref name="Sengupta">{{cite journal | vauthors = Sengupta P, Garrity P | title = Sensing temperature | journal = Current Biology | volume = 23 | issue = 8 | pages = R304-7 | date = April 2013 | pmid = 23618661 | pmc = 3685181 | doi = 10.1016/j.cub.2013.03.009 }}</ref> Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, the [[heat-shock response]]. Such response is triggered when high temperatures cause the dissociation of inactive [[HSF1]] from complexes with [[heat shock proteins]] [[Hsp40]]/[[Hsp70]] and [[Hsp90]]. With help from the [[ncRNA]] ''hsr1'', HSF1 then trimerizes, becoming active and upregulating the expression of its target genes.<ref>{{cite journal | vauthors = Shamovsky I, Ivannikov M, Kandel ES, Gershon D, Nudler E | title = RNA-mediated response to heat shock in mammalian cells | journal = Nature | volume = 440 | issue = 7083 | pages = 556–60 | date = March 2006 | pmid = 16554823 | doi = 10.1038/nature04518 | bibcode = 2006Natur.440..556S | s2cid = 4311262 }}</ref> Many other thermosensory mechanisms exist in both [[prokaryotes]] and [[eukaryotes]].<ref name="Sengupta" /> ===Light=== {{Main|Visual phototransduction}} In mammals, [[light]] controls the sense of [[Visual perception|sight]] and the [[circadian clock]] by activating light-sensitive proteins in [[photoreceptor cell]]s in the [[eye]]'s [[retina]]. In the case of vision, light is detected by [[rhodopsin]] in [[rod cells|rod]] and [[cone cells]].<ref name=burns>{{cite journal | vauthors = Burns ME, Arshavsky VY | title = Beyond counting photons: trials and trends in vertebrate visual transduction | journal = Neuron | volume = 48 | issue = 3 | pages = 387–401 | date = November 2005 | pmid = 16269358 | doi = 10.1016/j.neuron.2005.10.014 | doi-access = free }}</ref> In the case of the circadian clock, a different [[photopigment]], [[melanopsin]], is responsible for detecting light in [[intrinsically photosensitive retinal ganglion cells]].<ref>{{cite journal | vauthors = Berson DM | title = Phototransduction in ganglion-cell photoreceptors | journal = Pflügers Archiv | volume = 454 | issue = 5 | pages = 849–55 | date = August 2007 | pmid = 17351786 | doi = 10.1007/s00424-007-0242-2 | doi-access = free }}</ref> ==Receptors== Receptors can be roughly divided into two major classes: [[intracellular]] and [[extracellular]] receptors. ===Extracellular receptors=== Extracellular receptors are [[transmembrane protein|integral transmembrane protein]]s 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 region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in the [[Chemical conformation|conformation]] of the inside part of the receptor, a process sometimes called "receptor activation".<ref>{{cite web| url = http://www.bio-balance.com/JMGM_article.pdf| title = A molecular model for receptor activation}}</ref> This results in either the activation of an enzyme domain of 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 [[Eukaryote|eukaryotic]] cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include [[tyrosine kinase]] and [[phosphatase]]s. Often such enzymes are covalently linked to the receptor. Some of them create [[second messenger]]s such as [[cyclic AMP]] and [[Inositol triphosphate|IP<sub>3</sub>]], the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with [[Signal transducing adaptor protein|adaptor protein]]s that facilitate signaling protein interactions and coordination of signaling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules. Many adaptor proteins and enzymes activated as part of signal transduction possess specialized [[structural domain|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]]. PIP<sub>3</sub> and other phosphoinositides do the same thing to the [[Pleckstrin homology domain]]s of proteins such as the kinase protein [[AKT]]. ====G protein–coupled receptors==== {{Main|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]]. With nearly 800 members, this is the largest family of membrane proteins and receptors in mammals. Counting all animal species, they add up to over 5000.<ref name="F2005">{{cite journal | vauthors = Fredriksson R, Schiöth HB | title = The repertoire of G-protein-coupled receptors in fully sequenced genomes | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1414–25 | date = May 2005 | pmid = 15687224 | doi = 10.1124/mol.104.009001 | s2cid = 7938806 }}</ref> Mammalian GPCRs are classified into 5 major families: [[Rhodopsin-like receptors|rhodopsin-like]], [[Secretin receptor family|secretin-like]], [[Metabotropic glutamate receptor|metabotropic glutamate]], [[Adhesion-GPCR|adhesion]] and [[frizzled]]/[[smoothened]], with a few GPCR groups being difficult to classify due to low sequence similarity, e.g. [[vomeronasal receptor]]s.<ref name="F2005" /> Other classes exist in eukaryotes, such as the ''[[Dictyostelium]]'' [[cyclic AMP receptors]] and [[fungal mating pheromone receptors]].<ref name="F2005" /> Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; the G protein exists as a heterotrimer consisting of Gα, Gβ, and Gγ subunits.<ref name=" pmid=21873996 ">{{cite journal | vauthors = Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nature Chemical Biology | volume = 7 | issue = 10 | pages = 740–7 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref> 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.<ref>{{cite book| first1 = Jeremy M. | last1 = Berg | first2 = John L. | last2 = Tymoczko | first3 = Lubert | last3 = Stryer | first4 = Neil D. | last4 = Clarke | name-list-style = vanc |title=Biochemistry|publisher=W.H. Freeman|location=San Francisco|year=2002|isbn=978-0-7167-4954-7|url=https://archive.org/details/biochemistry200100jere}}</ref> The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as [[phospholipase]]s and [[ion channels]], the latter permitting the release of second messenger molecules.<ref>{{cite journal|vauthors=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|doi=10.3748/wjg.v12.i48.7753 |pmc=4087537 |doi-access=free }}</ref> 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; e.g. via protein kinase phosphorylation or b-arrestin-dependent internalization. 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 [[gene expression|expression]] of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development.<ref name=burger>{{cite journal | vauthors = Burger M, Burger JA, Hoch RC, Oades Z, Takamori H, Schraufstatter IU | title = Point mutation causing constitutive signaling of CXCR2 leads to transforming activity similar to Kaposi's sarcoma herpesvirus-G protein-coupled receptor | journal = Journal of Immunology | volume = 163 | issue = 4 | pages = 2017–22 | date = August 1999 | doi = 10.4049/jimmunol.163.4.2017 | pmid = 10438939 | s2cid = 45743458 | doi-access = free }}</ref> ====Tyrosine, Ser/Thr and Histidine-specific protein kinases==== [[Receptor tyrosine kinase]]s (RTKs) are transmembrane proteins with an intracellular [[kinase]] domain and an extracellular domain that binds [[ligand]]s; examples include [[growth factor]] receptors such as the [[insulin|insulin receptor]].<ref name=LiHris>{{cite journal | vauthors = 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 | date = May 2006 | pmid = 16700535 | pmc = 4301406 | doi = 10.1021/bi060609y }}</ref> To perform signal transduction, RTKs need to form [[protein dimer|dimer]]s in the [[plasma membrane]];<ref name=Schlessinger1988>{{cite journal | vauthors = Schlessinger J | title = Signal transduction by allosteric receptor oligomerization | journal = Trends in Biochemical Sciences | volume = 13 | issue = 11 | pages = 443–7 | date = November 1988 | pmid = 3075366 | doi = 10.1016/0968-0004(88)90219-8 }}</ref> the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the auto[[phosphorylation]] of [[tyrosine]] residues within the intracellular kinase domains of the RTKs, causing conformational changes. Subsequent to this, the receptors' kinase domains are activated, initiating [[phosphorylation]] signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as [[cell differentiation]] and [[metabolism]].<ref name=LiHris/> Many Ser/Thr and dual-specificity [[protein kinases]] are important for signal transduction, either acting downstream of [receptor tyrosine kinases], or as membrane-embedded or cell-soluble versions in their own right. The process of signal transduction involves around 560 known [[protein kinases]] and [[pseudokinases]], encoded by the human [[kinome]]<ref name="pmid12471243">{{cite journal | vauthors = Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S | title = The protein kinase complement of the human genome | journal = Science | volume = 298 | issue = 5600 | pages = 1912–34 | date = December 2002 | pmid = 12471243 | doi = 10.1126/science.1075762 | bibcode = 2002Sci...298.1912M | s2cid = 26554314 }}</ref><ref name="pmid24818526">{{cite journal | vauthors = Reiterer V, Eyers PA, Farhan H | title = Day of the dead: pseudokinases and pseudophosphatases in physiology and disease | journal = Trends in Cell Biology | volume = 24 | issue = 9 | pages = 489–505 | date = September 2014 | pmid = 24818526 | doi = 10.1016/j.tcb.2014.03.008 }}</ref> 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 superfamily|Ras]], [[Rho family of GTPases|Rho]], and Raf families, referred to collectively as [[small G protein]]s. 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 factor]]s 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 [[gene expression|expression]] of receptors that exist in a constitutively activated state; such mutated genes may act as [[oncogenes]].<ref name=roskoski>{{cite journal | vauthors = Roskoski R | title = The ErbB/HER receptor protein-tyrosine kinases and cancer | journal = Biochemical and Biophysical Research Communications | volume = 319 | issue = 1 | pages = 1–11 | date = June 2004 | pmid = 15158434 | doi = 10.1016/j.bbrc.2004.04.150 }}</ref> [[Histidine kinase|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.<ref>{{cite journal | vauthors = Wolanin PM, Thomason PA, Stock JB | title = Histidine protein kinases: key signal transducers outside the animal kingdom | journal = Genome Biology | volume = 3 | issue = 10 | pages = REVIEWS3013 | date = September 2002 | pmid = 12372152 | pmc = 244915 | doi = 10.1186/gb-2002-3-10-reviews3013 | doi-access = free }}</ref> ====Integrins==== {{Main|Integrin}} [[Image:Integrin sig trans overview.jpeg|450px|thumb|right|An overview of integrin-mediated signal transduction, adapted from Hehlgens ''et al.'' (2007).<ref name=hehlgans>{{cite journal | vauthors = Hehlgans S, Haase M, Cordes N | title = Signalling via integrins: implications for cell survival and anticancer strategies | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1775 | issue = 1 | pages = 163–80 | date = January 2007 | pmid = 17084981 | doi = 10.1016/j.bbcan.2006.09.001 }}</ref>]] 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]].<ref name=hehlgans/> As shown in the adjacent picture, cooperative integrin-RTK signaling determines the timing of cellular survival, [[apoptosis]], [[cell growth|proliferation]], and [[Cellular differentiation|differentiation]]. Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such as [[epithelial cell]]s; 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 activated only in response to stimuli such as those received at the site of an [[inflammation|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.<ref name=gilcrease>{{cite journal | vauthors = Gilcrease MZ | title = Integrin signaling in epithelial cells | journal = Cancer Letters | volume = 247 | issue = 1 | pages = 1–25 | date = March 2007 | pmid = 16725254 | doi = 10.1016/j.canlet.2006.03.031 }}</ref> In plants, there are no bona fide integrin receptors identified to date; nevertheless, several integrin-like proteins were proposed based on structural homology with the metazoan receptors.<ref>{{cite journal | vauthors = Knepper C, Savory EA, Day B | title = Arabidopsis NDR1 is an integrin-like protein with a role in fluid loss and plasma membrane-cell wall adhesion | journal = Plant Physiology | volume = 156 | issue = 1 | pages = 286–300 | date = May 2011 | pmid = 21398259 | pmc = 3091050 | doi = 10.1104/pp.110.169656 }}</ref> Plants contain integrin-linked kinases that are very similar in their primary structure with the animal ILKs. In the experimental model plant ''[[Arabidopsis thaliana]]'', one of the integrin-linked kinase genes, ''ILK1'', has been shown to be a critical element in the plant immune response to signal molecules from bacterial pathogens and plant sensitivity to salt and osmotic stress.<ref name="Brauer 1470–1484">{{cite journal | vauthors = Brauer EK, Ahsan N, Dale R, Kato N, Coluccio AE, Piñeros MA, Kochian LV, Thelen JJ, Popescu SC | display-authors = 6 | title = The Raf-like Kinase ILK1 and the High Affinity K+ Transporter HAK5 Are Required for Innate Immunity and Abiotic Stress Response | journal = Plant Physiology | volume = 171 | issue = 2 | pages = 1470–84 | date = June 2016 | pmid = 27208244 | pmc = 4902592 | doi = 10.1104/pp.16.00035 }}</ref> ILK1 protein interacts with the high-affinity potassium transporter [[HAK5]] and with the calcium sensor CML9.<ref name="Brauer 1470–1484"/><ref>{{cite journal | vauthors = Popescu SC, Popescu GV, Bachan S, Zhang Z, Seay M, Gerstein M, Snyder M, Dinesh-Kumar SP | display-authors = 6 | title = Differential binding of calmodulin-related proteins to their targets revealed through high-density Arabidopsis protein microarrays | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 11 | pages = 4730–5 | date = March 2007 | pmid = 17360592 | pmc = 1838668 | doi = 10.1073/pnas.0611615104 | bibcode = 2007PNAS..104.4730P | doi-access = free }}</ref> ====Toll-like receptors==== {{main|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 [[TRIF#Function|TRAM]].<ref name=Yamamoto_2003a>{{cite journal | vauthors = Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S | display-authors = 6 | title = Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway | journal = Science | volume = 301 | issue = 5633 | pages = 640–3 | date = August 2003 | pmid = 12855817 | doi = 10.1126/science.1087262 | bibcode = 2003Sci...301..640Y | s2cid = 19276476 | doi-access = free }}</ref><ref name=Yamamoto_2003b>{{cite journal | vauthors = Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S | display-authors = 6 | title = TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway | journal = Nature Immunology | volume = 4 | issue = 11 | pages = 1144–50 | date = November 2003 | pmid = 14556004 | doi = 10.1038/ni986 | s2cid = 13016860 }}</ref><ref name=Yamamoto_2002>{{cite journal | vauthors = Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S | display-authors = 6 | 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 | date = November 2002 | pmid = 12447441 | doi = 10.1038/nature01182 | bibcode = 2002Natur.420..324Y | s2cid = 16163262 }}</ref> These adapters activate other intracellular molecules such as [[IRAK1]], [[IRAK4]], [[TANK-binding kinase 1|TBK1]], and [[IKKi]] that amplify the signal, eventually leading to the [[signal induction|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 channels==== {{Main|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 the opening of these channels 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 Ca<sup>2+</sup>; 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 receptors=== {{Main|Intracellular receptor}} Intracellular receptors, such as [[nuclear receptor]]s and [[cytoplasm|cytoplasmic receptors]], are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar 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 [[cell nucleus|nucleus]], altering gene expression. Activated nuclear receptors attach to the DNA at receptor-specific [[hormone response element|hormone-responsive element]] (HRE) sequences, located in the [[promotor (biology)|promoter]] region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of [[gene expression]]. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor. Nucleic receptors have DNA-binding domains containing [[zinc finger]]s 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 [[protein dimer|dimerization]] of nucleic receptors prior to binding and providing structures for [[transactivation]] used for communication with the translational apparatus. [[Steroid receptor]]s are a subclass of nuclear receptors located primarily within the cytosol. In the absence of steroids, they associate in an aporeceptor complex containing [[chaperone protein|chaperone]] or [[heatshock protein]]s (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to [[protein folding|fold]] in a way such that the [[signal peptide|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. Receptor 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 (biology)|crosstalk]]. [[Retinoic acid receptor]]s 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 [[Protein precursor|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 [[Pattern recognition receptor|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 [[RIPK2|RIP2 kinase]] that activates [[NF-κB]] signaling, whereas others like [[NALP3]] interact with inflammatory [[caspase]]s and initiate processing of particular [[cytokine]]s like [[interleukin-1]]β.<ref>{{cite journal | vauthors = Delbridge LM, O'Riordan MX | title = Innate recognition of intracellular bacteria | journal = Current Opinion in Immunology | volume = 19 | issue = 1 | pages = 10–6 | date = February 2007 | pmid = 17126540 | doi = 10.1016/j.coi.2006.11.005 }}</ref><ref name = "Vander_1998" /> ==Second messengers== {{Main|Second messenger system}} First messengers are the signaling molecules (hormones, neurotransmitters, and paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response. In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction. ===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]]<ref>{{cite journal | vauthors = Wilson CH, Ali ES, Scrimgeour N, Martin AM, Hua J, Tallis GA, Rychkov GY, Barritt GJ | display-authors = 6 | title = Steatosis inhibits liver cell store-operated Ca²⁺ entry and reduces ER Ca²⁺ through a protein kinase C-dependent mechanism | journal = The Biochemical Journal | volume = 466 | issue = 2 | pages = 379–90 | date = March 2015 | pmid = 25422863 | doi = 10.1042/bj20140881 }}</ref> and the [[mitochondria]]. Two combined receptor/ion channel proteins control the transport of calcium: the [[Inositol triphosphate receptor|InsP<sub>3</sub>-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 InsP<sub>3</sub> 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. ===Lipid messengers=== 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 [[diglyceride|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 [[Nitric oxide synthase|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 the relaxation of blood vessels, [[apoptosis]], and penile [[erection]]s. ===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 [[organic semiconductors|semiconductive]] biological macromolecules.<ref name="Forman_2009">{{cite journal | vauthors = Forman HJ | title = Signal transduction and reactive species | journal = Free Radical Biology & Medicine | volume = 47 | issue = 9 | pages = 1237–8 | date = November 2009 | pmid = 19735727 | doi = 10.1016/j.freeradbiomed.2009.09.002 }}</ref> ==Cellular responses== Gene activations<ref name=lalli>{{cite journal | vauthors = Lalli E, Sassone-Corsi P | title = Signal transduction and gene regulation: the nuclear response to cAMP | journal = The Journal of Biological Chemistry | volume = 269 | issue = 26 | pages = 17359–62 | date = July 1994 | doi = 10.1016/S0021-9258(17)32442-0 | pmid = 8021233 | doi-access = free }}</ref> and metabolism alterations<ref name=rosen>{{cite journal | vauthors = Rosen OM | title = After insulin binds | journal = Science | volume = 237 | issue = 4821 | pages = 1452–8 | date = September 1987 | pmid = 2442814 | doi = 10.1126/science.2442814 | bibcode = 1987Sci...237.1452R }}</ref> 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<ref name=rosen/> 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]].<ref name=massaque>{{cite journal | vauthors = Massagué J, Gomis RR | title = The logic of TGFbeta signaling | journal = FEBS Letters | volume = 580 | issue = 12 | pages = 2811–20 | date = May 2006 | pmid = 16678165 | doi = 10.1016/j.febslet.2006.04.033 | doi-access = free }}</ref> 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 dysregulation. Three basic signals determine cellular growth: * Stimulatory (growth factors) ** Transcription dependent response<br />For example, steroids act directly as transcription factor (gives slow response, as transcription factor must bind DNA, which needs to be transcribed. Produced mRNA needs to be translated, and the produced protein/peptide can undergo [[posttranslational modification]] (PTM)) ** Transcription independent response<br />For example, [[epidermal growth factor]] (EGF) binds the [[epidermal growth factor receptor]] (EGFR), which causes dimerization and autophosphorylation of the EGFR, which in turn activates the intracellular signaling pathway .<ref name=sako>{{cite journal | vauthors = Sako Y, Minoghchi S, Yanagida T | title = Single-molecule imaging of EGFR signalling on the surface of living cells | journal = Nature Cell Biology | volume = 2 | issue = 3 | pages = 168–72 | date = March 2000 | pmid = 10707088 | doi = 10.1038/35004044 | s2cid = 25515586 }}</ref> * Inhibitory (cell-cell contact) * Permissive (cell-matrix interactions) The combination of these signals is integrated into altered cytoplasmic machinery which leads to altered cell behaviour. ==Major pathways== {{Further|List of signalling pathways}} [[File:How to read signal transduction diagrams.png|thumb|How to read signal transduction diagrams, what does normal arrow and flathead arrow means.]] [[File:Elements of Signal transduction cascade networking.png|thumb|Elements of Signal transduction cascade networking]] Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses. * [[MAPK/ERK pathway]]: A pathway that couples intracellular responses to the binding of [[growth factor]]s to [[cell (biology)|cell]] surface [[Receptor (biochemistry)|receptor]]s.&nbsp; This pathway is very complex and includes many [[protein]] components.<ref name=Orton2005>{{cite journal | vauthors = Orton RJ, Sturm OE, Vyshemirsky V, Calder M, Gilbert DR, Kolch W | title = Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway | journal = The Biochemical Journal | volume = 392 | issue = Pt 2 | pages = 249–61 | date = December 2005 | pmid = 16293107 | pmc = 1316260 | doi = 10.1042/BJ20050908 }}</ref>&nbsp; In many cell types, activation of this pathway promotes [[cell division]], and many forms of [[cancer]] are associated with aberrations in it.<ref>{{cite journal | vauthors = Vogelstein B, Kinzler KW | title = Cancer genes and the pathways they control | journal = Nature Medicine | volume = 10 | issue = 8 | pages = 789–99 | date = August 2004 | pmid = 15286780 | doi = 10.1038/nm1087 | s2cid = 205383514 }}</ref> * [[cAMP-dependent pathway]]: In humans, cAMP works by activating protein kinase A (PKA, [[cAMP-dependent protein kinase]]) (see picture), and, thus, further effects depend mainly on [[function of cAMP-dependent protein kinase|cAMP-dependent protein kinase]], which vary based on the type of cell. * [[IP3/DAG pathway|IP<sub>3</sub>/DAG pathway]]: PLC cleaves the [[phospholipid]] [[phosphatidylinositol 4,5-bisphosphate]] (PIP2), yielding [[diacyl glycerol]] (DAG) and [[inositol 1,4,5-triphosphate]] (IP<sub>3</sub>).&nbsp; DAG remains bound to the membrane, and IP<sub>3</sub> is released as a soluble structure into the [[cytosol]].&nbsp; IP<sub>3</sub> then diffuses through the cytosol to bind to [[Inositol triphosphate receptor|IP<sub>3</sub> receptors]], particular [[calcium channel]]s in the [[endoplasmic reticulum]] (ER).&nbsp; These channels are specific to [[calcium]] and allow the passage of only calcium to move through.&nbsp; This causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and activity.<ref name=alberts/>&nbsp; In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate other molecules, leading to altered cellular activity.&nbsp; End-effects include taste, manic depression, tumor promotion, etc.<ref name="alberts">{{cite book|vauthors=Alberts B, Lewis J, Raff M, Roberts K, Walter P |title=Molecular biology of the cell|url=https://archive.org/details/molecularbiolog000wils |url-access=registration |publisher=Garland Science|location=New York|edition=4th|year=2002|isbn=978-0-8153-3218-3}}</ref> ==History== [[Image:Signal transduction publications graph.jpeg|400px|thumb|right|Occurrence of the term "signal transduction" in [[MEDLINE]]-indexed papers since 1977]] The earliest notion of signal transduction can be traced back to 1855, when [[Claude Bernard]] proposed that ductless glands such as the [[spleen]], the [[thyroid gland|thyroid]] and [[adrenal gland]]s, were responsible for the release of "internal secretions" with physiological effects.<ref name="HCB1">Bradshaw & Dennis (2010) p. 1.</ref> Bernard's "secretions" were later named "[[hormones]]" by [[Ernest Starling]] in 1905.<ref>{{cite journal | vauthors = Tata JR | title = One hundred years of hormones | journal = EMBO Reports | volume = 6 | issue = 6 | pages = 490–6 | date = June 2005 | pmid = 15940278 | pmc = 1369102 | doi = 10.1038/sj.embor.7400444 }}</ref> Together with [[William Bayliss]], Starling had discovered [[secretin]] in 1902.<ref name="HCB1" /> Although many other hormones, most notably [[insulin]], were discovered in the following years, the mechanisms remained largely unknown. The discovery of [[nerve growth factor]] by [[Rita Levi-Montalcini]] in 1954, and [[epidermal growth factor]] by [[Stanley Cohen (biochemist)|Stanley Cohen]] in 1962, led to more detailed insights into the molecular basis of cell signaling, in particular [[growth factor]]s.<ref>{{cite journal | vauthors = Cowan WM | title = Viktor Hamburger and Rita Levi-Montalcini: the path to the discovery of nerve growth factor | journal = Annual Review of Neuroscience | volume = 24 | issue = 1 | pages = 551–600 | date = March 2001 | pmid = 11283321 | doi = 10.1146/annurev.neuro.24.1.551 | s2cid = 6747529 }}</ref> Their work, together with [[Earl Wilbur Sutherland]]'s discovery of [[cyclic AMP]] in 1956, prompted the redefinition of [[endocrine signaling]] to include only signaling from glands, while the terms [[autocrine]] and [[paracrine]] began to be used.<ref name="HCB2">Bradshaw & Dennis (2010) p. 2.</ref> Sutherland was awarded the 1971 [[Nobel Prize in Physiology or Medicine]], while Levi-Montalcini and Cohen shared it in 1986. 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 is a transducer that accepts glucagon molecules and affects the cell.<ref name=rodbell>{{cite journal | vauthors = Rodbell M | title = The role of hormone receptors and GTP-regulatory proteins in membrane transduction | journal = Nature | volume = 284 | issue = 5751 | pages = 17–22 | date = March 1980 | pmid = 6101906 | doi = 10.1038/284017a0 | bibcode = 1980Natur.284...17R | s2cid = 5650340 }}</ref> For this, he shared the 1994 [[Nobel Prize in Physiology or Medicine]] with [[Alfred G. Gilman]]. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in 1972.<ref name=rensing>{{cite journal | vauthors = Rensing L | title = Periodic geophysical and biological signals as Zeitgeber and exogenous inducers in animal organisms | journal = International Journal of Biometeorology | volume = 16 Suppl | pages = 113–25 | year = 1972 | pmid = 4621276 }}</ref> Some early articles used the terms ''signal transmission'' and ''sensory transduction''.<ref name=tonndorf>{{cite journal | vauthors = Tonndorf J | title = Davis-1961 revisited. Signal transmission in the cochlear hair cell-nerve junction | journal = Archives of Otolaryngology | volume = 101 | issue = 9 | pages = 528–35 | date = September 1975 | pmid = 169771 | doi = 10.1001/archotol.1975.00780380006002 }}</ref><ref name=ashcroft>{{cite journal | vauthors = Ashcroft SJ, Crossley JR, Crossley PC | title = The effect of N-acylglucosamines on the biosynthesis and secretion of insulin in the rat | journal = The Biochemical Journal | volume = 154 | issue = 3 | pages = 701–7 | date = March 1976 | pmid = 782447 | pmc = 1172772 | doi = 10.1042/bj1540701 }}</ref> In 2007, a total of 48,377 scientific papers—including 11,211 [[review journal|review papers]]—were published on the subject. The term first appeared in a paper's title in 1979.<ref name=hildebrand>{{cite journal | vauthors = Hildebrand E | title = What does Halobacterium tell us about photoreception? | journal = Biophysics of Structure and Mechanism | volume = 3 | issue = 1 | pages = 69–77 | date = April 1977 | pmid = 857951 | doi = 10.1007/BF00536457 | s2cid = 62775788 }}</ref><ref name=kenny>{{cite journal | vauthors = Kenny JJ, Martínez-Maza O, Fehniger T, Ashman RF | title = Lipid synthesis: an indicator of antigen-induced signal transduction in antigen-binding cells | journal = Journal of Immunology | volume = 122 | issue = 4 | pages = 1278–84 | date = April 1979 | doi = 10.4049/jimmunol.122.4.1278 | pmid = 376714 | s2cid = 29355685 | doi-access = free }}</ref> Widespread use of the term has been traced to a 1980 review article by Rodbell:<ref name=rodbell/><ref name=gomperts>{{cite book | vauthors = Gomperts BD, Kramer IM, Tatham PE | title = Signal transduction | publisher = Academic Press | year = 2002 | isbn = 978-0-12-289631-6 }}</ref> Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.<ref name = "Vander_1998">{{cite book| first1 = Arthur J | last1 = Vander | first2 = James | last2 = Sherman | first3 = Dorothy | last3 = Luciano | name-list-style = vanc |title=Human Physiology | edition = 7th |year=1998 |publisher=McGraw-Hill |isbn=978-0-07-067065-5 |pages=159–60 }}</ref> ===Signal transduction in [[Immunology]]=== The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology. The relevant events begin with the sequencing of [[myeloma protein]] light chains, which are found in abundance in the urine of individuals with [[multiple myeloma]]. Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or the [[Fragment crystallizable region]]).<ref>Steiner, L A (1996) Immunoglobulin evolution, 30 years on. Glycobiology 6 , 649-656</ref> An analysis of multiple V region sequences by Wu and Kabat <ref>Wu, T T, Kabat, E A (1970) An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132: 211-250</ref> identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of biological function through the Fc domain. Crystallization of an IgG molecule soon followed <ref>Sarma, V R, Silverton, E W, Davies, D R, Terry W D (1971) The three-dimensional structure at 6 A resolution of a human gamma G1 immunoglobulin molecule, J Biol. Chem. 246 (11) 3752- 9</ref> ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution. The biological significance of these developments was encapsulated in the theory of [[clonal selection]]<ref>Burnet, F M (1976) A modification of Jerne's theory of antibody production using the concept of clonal selection. CA: A Cancer Journal for Clinicians 26 (2) 119–21</ref> which holds that a [[B cell]] has on its surface immunoglobulin receptors whose antigen-binding site is identical to that of antibodies that are secreted by the cell when it encounters an antigen, and more specifically a particular B cell clone secretes antibodies with identical sequences. The final piece of the story, the [[Fluid mosaic model]] of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction; viz, receptor dimerization. The first hints of this were obtained by Becker et al <ref>Becker, K E, Ishizaka, T, Metzger, H, Ishizaka, K and Grimley, P M (1973) Surface IgE on Human Basophils during histamine release. J Exp med, 138, 394-408</ref> who demonstrated that the extent to which human [[basophils]]—for which bivalent [[Immunoglobulin E]] (IgE) functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalent [[ligand]] is used. The latter observation was consistent with earlier findings by Fanger et al.<ref>Fanger, M W, Hart, D A, Wells, J V, and Nisonoff, A J (1970) Requirement for cross-linkage in the stimulation of transformation of rabbit peripheral lymphocytes by antiglobulin reagents J. Immun., 105, 1484 - 92</ref> These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in <ref>Klemm J D, Schreiber S L, Crabtree G R (1998) Ann. Rev. Immunol. Dimerization as a regulatory mechanism in signal transduction 16: 569-592</ref>) in a variety of cell types, including B cells. Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell <ref>Bell, G I (1974) Model for the binding of multivalent antigens to cells, Nature Lond. 248, 430</ref> which resolved an apparent paradox: clustering forms stable networks; i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increase as the immune response progresses. A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed by [[DeLisi]] and Perelson <ref>DeLisi, C and Perelson A (1976). The kinetics of aggregation phenomena, J. theor. Biol. 62, 159-210</ref> who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand. Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators,<ref>Dembo, M and Goldstein, B (1978) Theory of equilibrium binding of symmetric bivalent haptens to cell surface antibody: application to histamine release from basophils. The Journal of Immunology 121 (1), 345-353</ref><ref>Sobotka, A.K. Dembo, M, Goldstein, B and Lichtenstein, L M, (1979) Antigen-specific desensitization of human basophils The Journal of Immunology, 122 (2) 511-517</ref> all aimed at the analysis of dose-response patterns of immune cells and their biological correlates.<ref>Kagey-Sobotka, A, Dembo, M, Goldstein, B, Metzger, H and Lichtenstein, L M (1981) Qualitative characteristics of histamine release from human basophils by covalently cross-linked IgE. The Journal of Immunology 127 (6), 2285-2291</ref> For a recent review of clustering in immunological systems see.<ref>How does T cell receptor clustering impact signal transduction? Jesse Goyette, Daniel J. Nieves, Yuanqing Ma, Katharina Gaus Journal of Cell Science 2019 132:jcs226423 {{doi|10.1242/jcs.226423}} Published 11 February 2019</ref> Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is a detection and response to concentration gradients by bacteria <ref>MacNab, R., and D. E. Koshland, Jr. (1972). The gradient-sensing mechanism in bacterial chemotaxis. Proc. Natl. Acad. Sci. U.S.A. 69:2509-2512</ref>-–the classic mathematical theory appearing in.<ref>Berg, H C and Purcell, E M (1977) Physics of chemoreception, Biophys. J 20(2):193-219</ref> A recent account can be found in <ref>Kirsten Jung, Florian Fabiani, Elisabeth Hoyer, and Jürgen Lassak 2018 Bacterial transmembrane signaling systems and their engineering for biosensing Open Biol. Apr; 8(4): 180023</ref> == See also == * [[Signal transducing adaptor protein|Adaptor protein]] * [[Scaffold protein]] * [[Biosemiotics]] * [[Cell signaling]] * [[Gene regulatory network]] * [[Hormonal imprinting]] * [[Metabolic pathway]] * [[Protein–protein interaction]] * [[Two-component regulatory system]] == References == {{Reflist|33em}} == External links == {{Commons category|Signal transduction}} * [http://www.netpath.org/ Netpath - A curated resource of signal transduction pathways in humans] {{Webarchive|url=https://web.archive.org/web/20120920084537/http://www.netpath.org/ |date=2012-09-20 }} * [http://biochemweb.fenteany.com/signaling.shtml Signal Transduction - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology] * [http://www.gene-regulation.com/cgi-bin/pub/databases/transpath/search.cgi TRANSPATH(R)] - A database about signal transduction pathways * [https://www.science.org/journal/signaling ''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] {{Webarchive|url=https://web.archive.org/web/20130212205534/http://www.signaling-gateway.org/molecule/ |date=2013-02-12 }}, from Nature Publishing Group * [http://www.litinspector.org LitInspector] {{Webarchive|url=https://web.archive.org/web/20190511063551/http://www.litinspector.org/ |date=2019-05-11 }} - Signal transduction pathway mining in PubMed abstracts * Huaxian Chen, et al. [http://www.licor.com./bio/PDF/AppNote_AnalBiochem.pdf A Cell Based Immunocytochemical Assay For Monitoring Kinase Signaling Pathways And Drug Efficacy (PDF)] {{Webarchive|url=https://web.archive.org/web/20120222171511/http://www.licor.com/bio/PDF/AppNote_AnalBiochem.pdf |date=2012-02-22 }} Analytical Biochemistry 338 (2005) 136-142 * [http://www.redoxsignaling.com www.Redoxsignaling.com] * [http://www.grt.kyushu-u.ac.jp/spad/ Signaling PAthway Database] {{Webarchive|url=https://web.archive.org/web/20120917214110/http://www.grt.kyushu-u.ac.jp/spad/ |date=2012-09-17 }} - [[Kyushu University]] * [http://www.genome.jp/kegg/pathway/hsa/hsa04110.html Cell cycle - Homo sapiens (human)] {{Webarchive|url=https://web.archive.org/web/20121023011711/http://www.genome.jp/kegg/pathway/hsa/hsa04110.html |date=2012-10-23 }} - [[KEGG]] PATHWAY [http://www.genome.jp/kegg/pathway.html] * [https://web.archive.org/web/20070715233022/http://pid.nci.nih.gov/ Pathway Interaction Database] - [[National Cancer 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