Editing Signal transduction (section)

===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 |title=A molecular model for receptor activation |url=http://www.bio-balance.com/JMGM_article.pdf}}</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.{{cn|date=April 2025}}

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.{{cn|date=April 2025}}

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 |date=May 2005 |title=The repertoire of G-protein-coupled receptors in fully sequenced genomes |journal=Molecular Pharmacology |volume=67 |issue=5 |pages=1414–25 |doi=10.1124/mol.104.009001 |pmid=15687224 |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 |date=August 2011 |title=Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers |journal=Nature Chemical Biology |volume=7 |issue=10 |pages=740–7 |doi=10.1038/nchembio.642 |pmc=3177959 |pmid=21873996}}</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 |last=Berg |first=Jeremy M. |url=https://archive.org/details/biochemistry200100jere |title=Biochemistry |last2=Tymoczko |first2=John L. |last3=Stryer |first3=Lubert |last4=Clarke |first4=Neil D. |publisher=W.H. Freeman |year=2002 |isbn=978-0-7167-4954-7 |location=San Francisco |name-list-style=vanc}}</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 |year=2006 |title=Mechanisms of regulation and function of G-protein-coupled receptor kinases |journal=World J Gastroenterol |volume=12 |issue=48 |pages=7753–7 |doi=10.3748/wjg.v12.i48.7753 |pmc=4087537 |pmid=17203515 |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.{{cn|date=April 2025}}

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 |date=August 1999 |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 |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 |date=May 2006 |title=Role of receptor tyrosine kinase transmembrane domains in cell signaling and human pathologies |journal=Biochemistry |volume=45 |issue=20 |pages=6241–51 |doi=10.1021/bi060609y |pmc=4301406 |pmid=16700535}}</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 |date=November 1988 |title=Signal transduction by allosteric receptor oligomerization |journal=Trends in Biochemical Sciences |volume=13 |issue=11 |pages=443–7 |doi=10.1016/0968-0004(88)90219-8 |pmid=3075366}}</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 |date=December 2002 |title=The protein kinase complement of the human genome |journal=Science |volume=298 |issue=5600 |pages=1912–34 |bibcode=2002Sci...298.1912M |doi=10.1126/science.1075762 |pmid=12471243 |s2cid=26554314}}</ref><ref name="pmid24818526">{{Cite journal |vauthors=Reiterer V, Eyers PA, Farhan H |date=September 2014 |title=Day of the dead: pseudokinases and pseudophosphatases in physiology and disease |journal=Trends in Cell Biology |volume=24 |issue=9 |pages=489–505 |doi=10.1016/j.tcb.2014.03.008 |pmid=24818526}}</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 |date=June 2004 |title=The ErbB/HER receptor protein-tyrosine kinases and cancer |journal=Biochemical and Biophysical Research Communications |volume=319 |issue=1 |pages=1–11 |doi=10.1016/j.bbrc.2004.04.150 |pmid=15158434}}</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 |date=September 2002 |title=Histidine protein kinases: key signal transducers outside the animal kingdom |journal=Genome Biology |volume=3 |issue=10 |pages=REVIEWS3013 |doi=10.1186/gb-2002-3-10-reviews3013 |pmc=244915 |pmid=12372152 |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 |date=January 2007 |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 |doi=10.1016/j.bbcan.2006.09.001 |pmid=17084981}}</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 |date=March 2007 |title=Integrin signaling in epithelial cells |journal=Cancer Letters |volume=247 |issue=1 |pages=1–25 |doi=10.1016/j.canlet.2006.03.031 |pmid=16725254}}</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 |date=May 2011 |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 |doi=10.1104/pp.110.169656 |pmc=3091050 |pmid=21398259}}</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 |display-authors=6 |vauthors=Brauer EK, Ahsan N, Dale R, Kato N, Coluccio AE, Piñeros MA, Kochian LV, Thelen JJ, Popescu SC |date=June 2016 |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 |doi=10.1104/pp.16.00035 |pmc=4902592 |pmid=27208244}}</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 |display-authors=6 |vauthors=Popescu SC, Popescu GV, Bachan S, Zhang Z, Seay M, Gerstein M, Snyder M, Dinesh-Kumar SP |date=March 2007 |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 |bibcode=2007PNAS..104.4730P |doi=10.1073/pnas.0611615104 |pmc=1838668 |pmid=17360592 |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 |display-authors=6 |vauthors=Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S |date=August 2003 |title=Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway |journal=Science |volume=301 |issue=5633 |pages=640–3 |bibcode=2003Sci...301..640Y |doi=10.1126/science.1087262 |pmid=12855817 |s2cid=19276476 |doi-access=free}}</ref><ref name="Yamamoto_2003b">{{Cite journal |display-authors=6 |vauthors=Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S |date=November 2003 |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 |doi=10.1038/ni986 |pmid=14556004 |s2cid=13016860}}</ref><ref name="Yamamoto_2002">{{Cite journal |display-authors=6 |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 |date=November 2002 |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 |bibcode=2002Natur.420..324Y |doi=10.1038/nature01182 |pmid=12447441 |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.