View source for Cell signaling

{{Short description|System of communication}}
{{For|the journal|Cellular Signalling}}
{{Lead too long|date=March 2025}}
In [[biology]], '''cell signaling''' ('''cell signalling''' in [[British English]]) is the [[Biological process|process]] by which a [[Cell (biology)|cell]] interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all [[Cell (biology)|cellular life]] in both [[prokaryote]]s and [[eukaryote]]s.

Typically, the signaling process involves three components: the signal, the receptor, and the effector.{{citation needed|date=January 2024}}

In biology, signals are mostly chemical in nature, but can also be physical cues such as [[pressure]], [[Membrane potential|voltage]], [[temperature]], or light. Chemical signals are molecules with the ability to bind and activate a specific [[Receptor (biochemistry)|receptor]]. These molecules, also referred to as [[Ligand (biochemistry)|ligands]], are chemically diverse, including [[ion]]s (e.g. Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup>, etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. Peptide and lipid ligands are particularly important, as most hormones belong to these classes of chemicals. Peptides are usually polar, hydrophilic molecules. As such they are unable to diffuse freely across the bi-lipid layer of the plasma membrane, so their action is mediated by a cell membrane bound receptor. On the other hand, liposoluble chemicals such as steroid hormones, can diffuse passively across the plasma membrane and interact with intracellular receptors.
Cell signaling can occur over short or long distances, and can be further classified as [[autocrine]], [[intracrine]], [[juxtacrine]], [[paracrine]], or [[endocrine]]. [[Autocrine signaling]] occurs when the chemical signal acts on the same cell that produced the signaling chemical.<ref>{{Cite book |last=Pandit |first=Nita K. |title=Introduction to the pharmaceutical sciences |date=2007 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-4478-2 |edition=1st |location=Baltimore, Md.}}</ref> Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell.<ref>{{Cite journal |last=Re |first=Richard N. |date=April 2003 |title=The intracrine hypothesis and intracellular peptide hormone action |journal=BioEssays |volume=25 |issue=4 |pages=401–409 |doi=10.1002/bies.10248 |pmid=12655647 }}</ref> Juxtacrine signaling occurs between physically adjacent cells.<ref>{{Cite book |last1=Gilbert |first1=Scott F. |title=Developmental biology |last2=Tyler |first2=Mary S. |last3=Kozlowski |first3=Ronald N. |date=2000 |publisher=Sinauer Assoc |isbn=978-0-87893-243-6 |edition=6th |location=Sunderland, Mass}}</ref> Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.<ref>{{Cite web |title=Hormones |url=https://medlineplus.gov/hormones.html |access-date=2023-11-28 |website=medlineplus.gov}}</ref>

[[Receptor (biochemistry)|Receptors]] are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the [[cytoplasm]], [[organelle]]s, and [[Cell nucleus|nucleus]]. Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. Receptors can be broadly classified into cell membrane receptors and intracellular receptors.
[[File:Cell Signaling Reception.jpg|thumb|Diagram of G-protein coupled reception]]
[[Cell surface receptor|Cell membrane receptors]] can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.

* Ion channels receptors are large transmembrane proteins with a ligand activated gate function. When these receptors are activated, they may allow or block passage of specific ions across the cell membrane. Most receptors activated by physical stimuli such as pressure or temperature belongs to this category.
* [[G protein-coupled receptor|G-protein receptors]] are multimeric proteins embedded within the plasma membrane. These receptors have extracellular, trans-membrane and intracellular [[Protein domain|domains]]. The extracellular domain is responsible for the interaction with a specific ligand. The intracellular domain is responsible for the initiation of a cascade of chemical reactions which ultimately triggers the specific cellular function controlled by the receptor.
* [[Enzyme-linked receptor]]s are transmembrane proteins with an extracellular domain responsible for binding a specific ligand and an intracellular domain with enzymatic or catalytic activity. Upon activation the enzymatic portion is responsible for promoting specific intracellular chemical reactions.

[[Intracellular receptor]]s have a different [[mechanism of action]]. They usually bind to lipid soluble ligands that diffuse passively through the plasma membrane such as steroid hormones. These ligands bind to specific cytoplasmic transporters that shuttle the hormone-transporter complex inside the nucleus where specific genes are activated and the synthesis of specific proteins is promoted.

The effector component of the signaling pathway begins with [[signal transduction]]. In this process, the signal, by interacting with the receptor, starts a series of molecular events within the cell leading to the final effect of the signaling process. Typically the final effect consists in the activation of an ion channel ([[ligand-gated ion channel]]) or the initiation of a [[second messenger system]] cascade that propagates the signal through the cell. Second messenger systems can amplify or modulate a signal, in which activation of a few receptors results in multiple secondary messengers being activated, thereby amplifying the initial signal (the first messenger). The [[Upstream and downstream (transduction)|downstream effects]] of these signaling pathways may include additional enzymatic activities such as [[Protease|proteolytic cleavage]], [[phosphorylation]], [[methylation]], and [[ubiquitinylation]].

Signaling molecules can be synthesized from various biosynthetic pathways and released through [[Passive transport|passive]] or [[active transport]]s, or even from [[cell damage]].

Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of [[Developmental biology|development]], [[tissue repair]], [[Immunity (medical)|immunity]], and [[homeostasis]]. Errors in signaling interactions may cause diseases such as [[cancer]], [[autoimmunity]], and [[diabetes]].

==Taxonomic range==
In many small organisms such as [[bacteria]], [[quorum sensing]] enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium ''[[Aliivibrio fischeri]]'', which [[bioluminescence|produces light]] when the population is dense enough.<ref name="Nealson-et-al-1970">{{cite journal |last1=Nealson |first1=K.H. |last2=Platt |first2=T. |last3=Hastings |first3=J.W. |year=1970 |title=Cellular control of the synthesis and activity of the bacterial luminescent system |url= |journal=[[Journal of Bacteriology]] |volume=104 |issue=1 |pages=313–22 |pmid=5473898 |pmc=248216 |doi=10.1128/jb.104.1.313-322.1970}}</ref> The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species.<ref name="Bassler-1999">{{Cite journal |last=Bassler |first=Bonnie L. |title=How bacteria talk to each other: regulation of gene expression by quorum sensing |journal=[[Current Opinion in Microbiology]] |volume=2 |issue=6 |pages=582–587 |doi=10.1016/s1369-5274(99)00025-9 |pmid=10607620|year=1999}}</ref>

In [[slime mold]]s, individual cells aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, known as an [[acrasin]]. The individuals move by [[chemotaxis]], i.e. they are attracted by the chemical gradient. Some species use [[cyclic AMP]] as the signal; others such as ''[[Polysphondylium violaceum]]'' use a [[dipeptide]] known as [[Dipeptide#Other dipeptides|glorin]].<ref>{{cite journal |last1=Shimomura |first1=O |last2=Suthers |first2=H L |last3=Bonner |first3=J T |title=Chemical identity of the acrasin of the cellular slime mold Polysphondylium violaceum. |journal=Proceedings of the National Academy of Sciences |date=December 1982 |volume=79 |issue=23 |pages=7376–7379 |doi=10.1073/pnas.79.23.7376 |pmid=6961416 |pmc=347342 |bibcode=1982PNAS...79.7376S |doi-access=free}}</ref>

In plants and animals, signaling between cells occurs either through release into the [[extracellular space]], divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling such as [[notch signaling]].<ref>{{cite book |last1=Gilbert |first1=Scott F. |title=Developmental Biology |edition=6th |date=2000 |publisher=Sinauer Associates |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10072/ |chapter=Juxtacrine Signaling }}</ref> Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule.<ref name=bruce>{{cite book |last1=Alberts |first1=Bruce |last2=Johnson |first2=Alexander |last3=Lewis |first3=Julian |last4=Raff |first4=Martin |last5=Roberts |first5=Keith |last6=Walter |first6=Peter |title=Molecular Biology of the Cell |edition=4th |date=2002 |publisher=Garland Science |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK26813/ |chapter=General Principles of Cell Communication }}</ref> [[Synapse|Synaptic]] signaling is a special case of paracrine signaling (for [[chemical synapse]]s) or juxtacrine signaling (for [[electrical synapse]]s) between [[neuron]]s and target cells.

==Extracellular signal==
===Synthesis and release===
[[File:Cell signalling.png|thumb|upright=1.6|Different types of extracellular signaling]]

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: [[lipid]]s, [[phospholipid]]s, [[amino acid]]s, [[monoamine]]s, [[protein]]s, [[glycoprotein]]s, or [[gaseous signaling molecules|gases]]. Signaling molecules binding surface receptors are generally large and [[hydrophilic]] (e.g. [[TRH]], [[Vasopressin]], [[Acetylcholine]]), while those entering the cell are generally small and [[hydrophobic]] (e.g. [[glucocorticoid]]s, [[thyroid hormone]]s, [[cholecalciferol]], [[retinoic acid]]), but important exceptions to both are numerous, and the same molecule can act both via surface receptors or in an intracrine manner to different effects.<ref name=bruce/> In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets.<ref name=Reece /> [[Hydrogen sulfide#Function in the body|Hydrogen sulfide]] is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: [[Biological functions of nitric oxide|nitric oxide]] and [[Carbon monoxide#Physiology|carbon monoxide]].<ref>{{cite book |last1=Cooper |first1=Geoffrey M. |title=The Cell: A Molecular Approach |edition=2nd |date=2000 |publisher=Sinauer Associates |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK9924/ |chapter=Signaling Molecules and Their Receptors }}</ref>

====Exocytosis====

[[Exocytosis]] is the process by which a cell transports [[molecule]]s such as [[neurotransmitter]]s and [[protein]]s out of the cell. As an [[active transport]] mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, [[endocytosis]], the process that brings substances into the cell, are used by all cells because most [[chemical substance]]s important to them are large [[chemical polarity|polar]] molecules that cannot pass through the [[hydrophobic]] portion of the [[cell membrane]] by [[passive transport]]. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called [[porosome]]s. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.<ref>{{cite journal |last1=Jena |first1=Bhanu |title=Porosome: the secretory portal in cells |journal=Biochemistry |date=2009 |volume=48 |issue=19 |pages=4009–4018 |publisher=ACS Publications |doi=10.1021/bi9002698 |pmid=19364126 |pmc=4580239 |language=English}}</ref>

In the context of [[neurotransmission]], neurotransmitters are typically released from [[synaptic vesicle]]s into the [[synaptic cleft]] via exocytosis; however, neurotransmitters can also be released via [[reverse transport]] through [[membrane transport protein]]s.{{citation needed|date=September 2023}}

===Forms of Cell Signaling===

====Autocrine====
[[File: Autocrine and Paracrine.png|thumb|upright=1.6|Differences between autocrine and paracrine signaling]]

[[Autocrine signaling]] involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself.<ref name = "one">{{cite book |last=Pandit |first=Nikita K. |title=Introduction To The Pharmaceutical Sciences |page=[https://archive.org/details/introductiontoph0000pand/page/238 238] |year=2007 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-4478-2 |url=https://archive.org/details/introductiontoph0000pand/page/238 }}</ref> This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

==== Intracrine ====
In [[Intracrine|intracrine signaling]], the signaling chemicals are produced inside the cell and bind to cytosolic or nuclear receptors without being secreted from the cell. The intracrine signals not being secreted outside of the cell is what sets apart intracrine signaling from the other cell signaling mechanisms such as autocrine signaling. In both autocrine and intracrine signaling, the signal has an effect on the cell that produced it.<ref>{{cite journal |last1=Rubinow |first1=Katya B. |title=An intracrine view of sex steroids, immunity, and metabolic regulation |journal=Molecular Metabolism |date=September 2018 |volume=15 |pages=92–103 |doi=10.1016/j.molmet.2018.03.001 |pmc=6066741 |pmid=29551633}}</ref>

====Juxtacrine====
[[Juxtacrine signalling|Juxtacrine signaling]] is a type of [[Cell (biology)|cell]]–cell or cell–[[extracellular matrix]] signaling in [[multicellular]] organisms that requires close contact. There are three types:
[[File:Forms of Cell Signaling.png|thumb|This image displays the different types of cell signaling]]

# A membrane [[ligand]] ([[protein]], [[oligosaccharide]], [[lipid]]) and a [[membrane protein]] of two adjacent cells [[Protein interaction|interact]].
# A communicating [[cell junction|junction]] links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
# An extracellular matrix [[glycoprotein]] and a membrane protein interact.

Additionally, in [[unicellular]] organisms such as [[bacteria]], juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some [[growth factor]]s, [[cytokine]] and [[chemokine]] cellular signals, playing an important role in the [[immune response]]. Juxtacrine signalling via direct membrane contacts is also present between neuronal cell bodies and motile processes of [[microglia]] both during development,<ref>{{cite journal |last1=Cserép |first1=Csaba |last2=Schwarcz |first2=Anett D. |last3=Pósfai |first3=Balázs |last4=László |first4=Zsófia I. |last5=Kellermayer |first5=Anna |last6=Környei |first6=Zsuzsanna |last7=Kisfali |first7=Máté |last8=Nyerges |first8=Miklós |last9=Lele |first9=Zsolt |last10=Katona |first10=István |date=September 2022 |title=Microglial control of neuronal development via somatic purinergic junctions |journal=Cell Reports |volume=40 |issue=12 |pages=111369 |doi=10.1016/j.celrep.2022.111369 |pmc=9513806 |pmid=36130488}}</ref> and in the adult brain.<ref>{{cite journal |last1=Cserép |first1=Csaba |last2=Pósfai |first2=Balázs |last3=Lénárt |first3=Nikolett |last4=Fekete |first4=Rebeka |last5=László |first5=Zsófia I. |last6=Lele |first6=Zsolt |last7=Orsolits |first7=Barbara |last8=Molnár |first8=Gábor |last9=Heindl |first9=Steffanie |last10=Schwarcz |first10=Anett D. |last11=Ujvári |first11=Katinka |last12=Környei |first12=Zsuzsanna |last13=Tóth |first13=Krisztina |last14=Szabadits |first14=Eszter |last15=Sperlágh |first15=Beáta |last16=Baranyi |first16=Mária |last17=Csiba |first17=László |last18=Hortobágyi |first18=Tibor |last19=Maglóczky |first19=Zsófia |last20=Martinecz |first20=Bernadett |last21=Szabó |first21=Gábor |last22=Erdélyi |first22=Ferenc |last23=Szipőcs |first23=Róbert |last24=Tamkun |first24=Michael M. |last25=Gesierich |first25=Benno |last26=Duering |first26=Marco |last27=Katona |first27=István |last28=Liesz |first28=Arthur |last29=Tamás |first29=Gábor |last30=Dénes |first30=Ádám |title=Microglia monitor and protect neuronal function through specialized somatic purinergic junctions |journal=Science |date=31 January 2020 |volume=367 |issue=6477 |pages=528–537 |doi=10.1126/science.aax6752 |pmid=31831638 |bibcode=2020Sci...367..528C |url=https://epub.ub.uni-muenchen.de/76442/1/Cserep_Posfai_et_al_accepted.pdf }}</ref>

====Paracrine====
[[File:Paracrine Signaling.jpg|thumb|This image depicts paracrine signaling, where a secretory cell releases signaling molecules that diffuse and trigger cellular responses in nearby target cells]]
In [[paracrine signaling]], a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the [[circulatory system]]; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate [[extracellular]] environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain. 

Paracrine signals such as [[retinoic acid]] target only cells in the vicinity of the emitting cell.<ref name="Duester">{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–31 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref> [[Neurotransmitter]]s represent another example of a paracrine signal.

Some signaling molecules can function as both a hormone and a neurotransmitter. For example, [[epinephrine]] and [[norepinephrine]] can function as hormones when released from the [[adrenal gland]] and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by [[neuron]]s to function as a neurotransmitter within the brain.<ref name="Cartford2004">{{cite journal | vauthors = Cartford MC, Samec A, Fister M, Bickford PC | title = Cerebellar norepinephrine modulates learning of delay classical eyeblink conditioning: evidence for post-synaptic signaling via PKA | journal = Learning & Memory | volume = 11 | issue = 6 | pages = 732–7 | year = 2004 | pmid = 15537737 | pmc = 534701 | doi = 10.1101/lm.83104 }}</ref> [[Estrogen]] can be released by the [[ovary]] and function as a hormone or act locally via paracrine or autocrine signaling.<ref name="Jesmin2004">{{cite journal | vauthors = Jesmin S, Mowa CN, Sakuma I, Matsuda N, Togashi H, Yoshioka M, Hattori Y, Kitabatake A | title = Aromatase is abundantly expressed by neonatal rat penis but downregulated in adulthood | journal = Journal of Molecular Endocrinology | volume = 33 | issue = 2 | pages = 343–59 | date = October 2004 | pmid = 15525594 | doi = 10.1677/jme.1.01548  | doi-access = free }}</ref>

Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different [[organ (biology)|organ]]s in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development.<ref>{{cite book |last1=Gilbert |first1=Scott F. |title=Developmental Biology |edition=6th |date=2000 |publisher=Sinauer Associates |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10071/ |chapter=Paracrine Factors }}</ref> The [[Conserved sequence|highly conserved]] receptors and pathways can be organized into four major families based on similar structures: [[fibroblast growth factor]] (FGF) family, [[Hedgehog signaling pathway|Hedgehog]] family, [[Wnt signaling pathway|Wnt]] family, and [[Transforming growth factor beta|TGF-β superfamily]]. Binding of a paracrine factor to its respective receptor initiates [[signal transduction]] cascades, eliciting different responses. 

====Endocrine====
[[File:Endocrine Signaling.jpg|thumb|This image displays endocrine signaling, the process by which endocrine glands produce hormones that are released into the bloodstream, allowing them to travel to distant target cells and bind to specific receptors, triggering a cellular response.]]
''[[Endocrine system|Endocrine]]'' signals are called hormones. [[Hormone|Hormones]] are produced by endocrine cells and they travel through the [[circulatory system|blood]] to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Endocrine signaling involves the release of hormones by internal [[gland]]s of an [[organism]] directly into the [[circulatory system]], regulating distant target organs. In [[vertebrate]]s, the [[hypothalamus]] is the neural control center for all endocrine systems. In [[humans]], the major [[endocrine gland]]s are the [[thyroid gland]] and the [[adrenal gland]]s. The study of the endocrine system and its disorders is known as [[endocrinology]].

==Receptors==
{{Main|Receptor (biochemistry)}}
[[File:Ligand-receptor interaction.png|thumb|upright=1.6|Transmembrane receptor working principle]]
Cells receive information from their neighbors through a class of proteins known as [[Receptor (biochemistry)|receptors]]. Receptors may bind with some molecules ([[Ligand (biochemistry)|ligands]]) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to [[intracellular receptor]]s, other elements, or stimulate [[enzyme]] activity (e.g. gasses), as in intracrine signaling.

Signaling molecules interact with a target cell as a ligand to [[cell surface receptor]]s, and/or by entering into the cell through its membrane or [[endocytosis]] for intracrine signaling. This generally results in the activation of [[second messenger]]s, leading to various physiological effects. In many mammals, early [[embryo]] cells exchange signals with cells of the [[uterus]].<ref name="Mohamed2005">{{cite journal | vauthors = Mohamed OA, Jonnaert M, Labelle-Dumais C, Kuroda K, Clarke HJ, Dufort D | title = Uterine Wnt/beta-catenin signaling is required for implantation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 24 | pages = 8579–84 | date = June 2005 | pmid = 15930138 | pmc = 1150820 | doi = 10.1073/pnas.0500612102 | bibcode = 2005PNAS..102.8579M | doi-access = free }}</ref> In the human [[gastrointestinal tract]], [[bacteria]] exchange signals with each other and with human [[epithelium|epithelial]] and [[immune system]] cells.<ref name="Clarke2005">{{cite journal|vauthors=Clarke MB, Sperandio V|date=June 2005|title=Events at the host-microbial interface of the gastrointestinal tract III. Cell-to-cell signaling among microbial flora, host, and pathogens: there is a whole lot of talking going on|journal=American Journal of Physiology. Gastrointestinal and Liver Physiology|volume=288|issue=6|pages=G1105–9|doi=10.1152/ajpgi.00572.2004|pmid=15890712}}</ref> For the yeast ''[[Saccharomyces cerevisiae]]'' during [[Mating of yeast|mating]], some cells send a peptide signal (mating factor [[pheromone]]s) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.<ref name="Lin2004">{{cite journal | vauthors = Lin JC, Duell K, Konopka JB | title = A microdomain formed by the extracellular ends of the transmembrane domains promotes activation of the G protein-coupled alpha-factor receptor | journal = Molecular and Cellular Biology | volume = 24 | issue = 5 | pages = 2041–51 | date = March 2004 | pmid = 14966283 | pmc = 350546 | doi = 10.1128/MCB.24.5.2041-2051.2004 }}</ref>

===Cell surface receptors===
{{See also|Ligand (biochemistry)|Receptor–ligand kinetics}}
Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma.<ref name="pmid17607357">{{cite journal | vauthors = Han R, Bansal D, Miyake K, Muniz VP, Weiss RM, McNeil PL, Campbell KP | title = Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury | journal = The Journal of Clinical Investigation | volume = 117 | issue = 7 | pages = 1805–13 | date = July 2007 | pmid = 17607357 | pmc = 1904311 | doi = 10.1172/JCI30848}}
* {{cite press release |date=July 6, 2007 |title=Faulty Cell Membrane Repair Causes Heart Disease |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2007/07/070703171935.htm}}</ref> These [[Transmembrane protein|trans-membrane]] receptors are able to transmit information from outside the cell to the inside because they [[Conformational change|change conformation]] when a specific ligand binds to it. There are three major types: [[Ligand-gated ion channels|Ion channel linked receptors]], [[G protein–coupled receptor]]s, and [[enzyme-linked receptor]]s.

====Ion channel linked receptors====
[[Image:AMPA receptor.png|right|thumb|The [[AMPA receptor]] bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, {{PDB|3KG2}}]]
Ion channel linked receptors are a group of [[transmembrane]] [[ion-channel]] proteins which open to allow ions such as [[sodium|Na<sup>+</sup>]], [[potassium|K<sup>+</sup>]], [[calcium|Ca<sup>2+</sup>]], and/or [[chloride|Cl<sup>−</sup>]] to pass through the membrane in response to the binding of a chemical messenger (i.e. a [[ligand (biochemistry)|ligand]]), such as a [[neurotransmitter]].<ref>{{cite web|url=https://www.genenames.org/cgi-bin/genefamilies/set/161|title=Gene Family: Ligand gated ion channels|publisher=HUGO Gene Nomenclature Committee}}</ref><ref>{{DorlandsDict|two/000019817|ligand-gated channel}}</ref><ref name="Purves" >{{cite book |author=Purves, Dale |author2=George J. Augustine |author3=David Fitzpatrick |author4=William C. Hall |author5=Anthony-Samuel LaMantia |author6=James O. McNamara |author7=Leonard E. White | title = Neuroscience. 4th ed. | publisher = Sinauer Associates | pages = 156–7 | year = 2008 | isbn = 978-0-87893-697-7}}</ref>

When a [[presynaptic neuron]] is excited, it releases a [[neurotransmitter]] from vesicles into the [[synaptic cleft]]. The neurotransmitter then binds to receptors located on the [[postsynaptic neuron]]. If these receptors are [[Ligand-gated ion channel|ligand-gated ion channels]] (LICs), a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a [[depolarization]], for an excitatory receptor response, or a [[hyperpolarization (biology)|hyperpolarization]], for an inhibitory response.

These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an [[allosteric regulation|allosteric]] binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at [[synapse]]s is to convert the chemical signal of [[presynaptic]]ally released neurotransmitter directly and very quickly into a [[postsynaptic]] electrical signal. Many LICs are additionally modulated by [[Allosteric modulator|allosteric ligands]], by [[channel blockers]], [[ion]]s, or the [[membrane potential]]. LICs are classified into three superfamilies which lack evolutionary relationship: [[cys-loop receptor]]s, [[Glutamate-gated ion channel family|ionotropic glutamate receptors]] and [[P2X purinoreceptor|ATP-gated channels]].

====G protein–coupled receptors====
[[File:PDB 1hzx 7TM Sketch Membrane.png|thumb|A G Protein-coupled receptor within the plasma membrane]]
G protein-coupled receptors are a large group of [[protein family|evolutionarily-related proteins]] that are [[cell surface receptor]]s that detect [[molecule]]s outside the [[cell (biology)|cell]] and activate cellular responses. Coupling with [[G protein]]s, they are called seven-transmembrane receptors because they pass through the [[cell membrane]] seven times. The G-protein acts as a "middle man" transferring the signal from its activated receptor to its target and therefore indirectly regulates that target protein.<ref name=trz>{{cite journal | vauthors = Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S | title = Action of molecular switches in GPCRs--theoretical and experimental studies | journal = Current Medicinal Chemistry | volume = 19 | issue = 8 | pages = 1090–109 | year = 2012 | pmid = 22300046 | pmc = 3343417 | doi = 10.2174/092986712799320556 }}  [[File:CC0-icon-80x15.png|50px]] Text was copied from this source, which is available under a [https://creativecommons.org/licenses/by/2.5/ Attribution 2.5 Generic (CC BY 2.5)] {{Webarchive|url=https://web.archive.org/web/20110222034809/http://creativecommons.org/licenses/by/2.5/ |date=22 February 2011 }} license.</ref>  Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to  the binding site within transmembrane helices (Rhodopsin-like family).  They are all activated by [[agonist]]s although a spontaneous auto-activation of an empty receptor can also be observed.<ref name=trz/>

G protein-coupled receptors are found only in [[eukaryote]]s, including [[yeast]], [[choanoflagellate]]s,<ref name="pmid12869759">{{cite journal | vauthors = King N, Hittinger CT, Carroll SB | title = Evolution of key cell signaling and adhesion protein families predates animal origins | journal = Science | volume = 301 | issue = 5631 | pages = 361–3 | date = July 2003 | pmid = 12869759 | doi = 10.1126/science.1083853 | bibcode = 2003Sci...301..361K }}</ref> and animals. The [[ligand (biochemistry)|ligands]] that bind and activate these receptors include light-sensitive compounds, [[odor]]s, [[pheromone]]s, [[hormone]]s, and [[neurotransmitter]]s, and vary in size from small molecules to peptides to large [[protein]]s. G protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors: [[CAMP-dependent pathway|cAMP signal pathway]] and [[phosphatidylinositol]] signal pathway.<ref name="Gilman_1987">{{cite journal | vauthors = Gilman AG | title = G proteins: transducers of receptor-generated signals | journal = Annual Review of Biochemistry | volume = 56 | issue = 1 | pages = 615–49 | year = 1987 | pmid = 3113327 | doi = 10.1146/annurev.bi.56.070187.003151 }}</ref> When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a [[guanine nucleotide exchange factor]] (GEF). The GPCR can then activate an associated [[G protein]] by exchanging the [[guanosine diphosphate|GDP]] bound to the G protein for a [[guanosine triphosphate|GTP]]. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type ([[Gs alpha subunit|G<sub>αs</sub>]], [[Gi alpha subunit|G<sub>αi/o</sub>]], [[Gq alpha subunit|G<sub>αq/11</sub>]], [[G12/G13 alpha subunits|G<sub>α12/13</sub>]]).<ref name="Wettschureck_2005">{{cite journal | vauthors = Wettschureck N, Offermanns S | title = Mammalian G proteins and their cell type specific functions | journal = Physiological Reviews | volume = 85 | issue = 4 | pages = 1159–204 | date = October 2005 | pmid = 16183910 | doi = 10.1152/physrev.00003.2005 }}</ref>{{rp|1160}}

G protein-coupled receptors are an important [[drug target]] and approximately 34%<ref name="Hauser_2018">{{cite journal | vauthors = Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM | title = Pharmacogenomics of GPCR Drug Targets | journal = Cell | volume = 172 | issue = 1–2 | pages = 41–54.e19 | date = January 2018 | pmid = 29249361 | pmc = 5766829 | doi = 10.1016/j.cell.2017.11.033 }}</ref> of all Food and Drug Administration (FDA) approved drugs target 108 members of this family.  The global sales volume for these drugs is estimated to be 180 billion US dollars {{As of|lc=y|1=2018}}.<ref name="Hauser_2018"/> It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.<ref name=trz/>

====Enzyme-linked receptors====
[[File: VEGF receptors.png| thumb|right | [[VEGF receptor|VEGF receptors]] are a type of enzyme-coupled receptors, specifically tyrosine kinase receptors]]
Enzyme-linked receptors (or catalytic receptors) are [[transmembrane receptors]] that, upon activation by an extracellular [[Ligand (biochemistry)|ligand]], causes [[enzymatic]] activity on the intracellular side.<ref name="Dudek2006">{{cite book|author=Ronald W. Dudek|title=High-yield cell and molecular biology|url=https://books.google.com/books?id=g-d--DOdnQAC&pg=PA19|access-date=16 December 2010|date=1 November 2006|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6887-0|pages=19–}}</ref> Hence a catalytic receptor is an [[integral membrane protein]] possessing both [[Enzyme|enzymatic]], [[catalysis|catalytic]], and [[Receptor (biochemistry)|receptor]] functions.<ref name="pmc2013840">{{cite journal |vauthors=Alexander SP, Mathie A, Peters JA | title = Catalytic Receptors | journal = Br. J. Pharmacol. | volume = 150 Suppl 1 | issue = S1| pages = S122–7 |date=February 2007 | pmc = 2013840 | doi = 10.1038/sj.bjp.0707205 }}</ref>

They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single [[transmembrane helix]].  The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell.{{citation needed|date=September 2023}} Examples of the enzymatic activity include:
* [[Receptor tyrosine kinase]], as in [[fibroblast growth factor receptor]]. Most enzyme-linked receptors are of this type.<ref>{{Cite web |url=http://darwin.nmsu.edu/~molbio/mcb520/lecture10.html |title=lecture10<!-- Bot generated title --> |access-date=2007-03-03 |archive-url=https://web.archive.org/web/20070525080552/http://darwin.nmsu.edu/~molbio/mcb520/lecture10.html |archive-date=2007-05-25 |url-status=dead }}</ref>
* [[Receptor protein serine/threonine kinase]], as in [[bone morphogenetic protein]]
* [[Guanylate cyclase]], as in [[atrial natriuretic factor receptor]]

=== Intracellular receptors ===
Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to [[Organelle|organelles]] or membranes. For example, the presence of [[Nuclear receptor|nuclear]] and mitochondrial receptors is well documented.<ref>{{Cite journal |last1=Lee |first1=Junghee |last2=Sharma |first2=Swati |last3=Kim |first3=Jinho |last4=Ferrante |first4=Robert J. |last5=Ryu |first5=Hoon |date=April 2008 |title=Mitochondrial Nuclear Receptors and Transcription Factors: Who's Minding the Cell? |journal=Journal of Neuroscience Research |volume=86 |issue=5 |pages=961–971 |doi=10.1002/jnr.21564 |pmc=2670446 |pmid=18041090}}</ref> The binding of a ligand to the intracellular receptor typically induces a response in the cell. Intracellular receptors often have a level of specificity, this allows the receptors to initiate certain responses when bound to a corresponding ligand.<ref>{{cite book |doi=10.1007/978-1-4757-4619-8_3 |chapter=Intracellular Receptors: Characteristics and Measurement |title=Biological Regulation and Development |date=1984 |last1=Clark |first1=James H. |last2=Peck |first2=Ernest J. |pages=99–127 |isbn=978-1-4757-4621-1 }}</ref> Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of [[DNA-binding protein|DNA binding proteins.]] Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of [[gene expression]].{{fact|date=February 2025}}

[[Steroid hormone receptor|Steroid hormone receptors]] are found in the [[cell nucleus|nucleus]], [[cytosol]], and also on the [[plasma membrane]] of target cells. They are generally [[intracellular receptor]]s (typically cytoplasmic or nuclear) and initiate [[signal transduction]] for [[steroid hormone]]s which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone [[receptor (biochemistry)|receptors]] are members of the [[nuclear receptor]] subfamily 3 (NR3) that include [[Estrogen receptor|receptors for estrogen]] (group NR3A)<ref name="pmid17132854">{{cite journal | vauthors = Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA | title = International Union of Pharmacology. LXIV. Estrogen receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 773–81 | date = Dec 2006 | pmid = 17132854 | doi = 10.1124/pr.58.4.8 }}</ref> and 3-ketosteroids (group NR3C).<ref name="pmid17132855">{{cite journal | vauthors = Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA | title = International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 782–97 | date = Dec 2006 | pmid = 17132855 | doi = 10.1124/pr.58.4.9 }}</ref>  In addition to nuclear receptors, several [[G protein-coupled receptor]]s and [[ion channel]]s act as [[cell surface receptor]]s for certain steroid hormones.

== Mechanisms of Receptor Down-Regulation ==
{{Further|Downregulation and upregulation}}
[[Receptor-mediated endocytosis|Receptor mediated endocytosis]] is common way of turning receptors "off". Endocytic [[Downregulation and upregulation|down regulation]] is regarded as a means for reducing receptor signaling.<ref>{{Cite journal |last1=Roepstorff |first1=Kirstine |last2=Grøvdal |first2=Lene |last3=Grandal |first3=Michael |last4=Lerdrup |first4=Mads |last5=van Deurs |first5=Bo |date=May 2008 |title=Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer |journal=Histochemistry and Cell Biology |volume=129 |issue=5 |pages=563–578 |doi=10.1007/s00418-008-0401-3 |pmc=2323030 |pmid=18288481}}</ref> The process involves the binding of a ligand to the receptor, which then triggers the formation of coated pits, the coated pits transform to coated vesicles and are transported to the [[endosome]].

Receptor Phosphorylation is another type of receptor down-regulation. Biochemical changes can reduce receptor affinity for a ligand.<ref>{{cite journal |last1=Li |first1=Xin |last2=Huang |first2=Yao |last3=Jiang |first3=Jing |last4=Frank |first4=Stuart J. |title=ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling |journal=Cellular Signalling |date=November 2008 |volume=20 |issue=11 |pages=2145–2155 |doi=10.1016/j.cellsig.2008.08.006 |pmid=18762250 |pmc=2613789 }}</ref>

Reducing the sensitivity of the receptor is a result of receptors being occupied for a long time. This results in a receptor adaptation in which the receptor no longer responds to the signaling molecule. Many receptors have the ability to change in response to ligand concentration.<ref>{{Cite journal |last=Schwartz |first=Alan L. |date=December 1995 |title=Receptor Cell Biology: Receptor-Mediated Endocytosis |journal=Pediatric Research |volume=38 |issue=6 |pages=835–843 |doi=10.1203/00006450-199512000-00003 |pmid=8618782 |doi-access=free }}</ref>

==Signal transduction pathways==
{{Further|Signal transduction | List of signalling pathways}}
When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplifying of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organism.<ref name=Reece>{{cite book|last1=Reece|first1=Jane B | name-list-style = vanc |title=Campbell Biology|date=Sep 27, 2010|publisher=Benjamin Cummings|isbn=978-0321558237|page=[https://archive.org/details/campbellbiologyj00reec/page/214 214]|url-access=registration|url=https://archive.org/details/campbellbiologyj00reec/page/214}}</ref>

In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter [[gamma-Aminobutyric acid|GABA]] can activate a cell surface receptor that is part of an [[ion channel]]. GABA binding to a [[GABAA receptor|GABA<sub>A</sub> receptor]] on a neuron opens a [[Chloride channel|chloride-selective ion channel]] that is part of the receptor. GABA<sub>A</sub> receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce [[action potential]]s. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate [[Physiology|physiological]] effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a [[signal transduction]] mechanism or pathway.<ref>{{cite journal | vauthors = Dinasarapu AR, Saunders B, Ozerlat I, Azam K, Subramaniam S | title = Signaling gateway molecule pages--a data model perspective | journal = Bioinformatics | volume = 27 | issue = 12 | pages = 1736–8 | date = June 2011 | pmid = 21505029 | pmc = 3106186 | doi = 10.1093/bioinformatics/btr190 }}</ref>

[[File:MAPKpathway diagram.svg|thumb|right|Key components of a signal transduction pathway ([[MAPK/ERK pathway]] shown)]]
A more complex signal transduction pathway is the MAPK/ERK pathway, which involves changes of [[protein–protein interaction]]s inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the [[cell cycle]] and [[Cell division|divide]]. Several of these receptors are [[kinase]]s that start to phosphorylate themselves and other proteins when binding to a ligand. This [[phosphorylation]] can generate a binding site for a different protein and thus induce protein–protein interaction. In this case, the ligand (called [[epidermal growth factor]], or EGF) binds to the receptor (called [[Epidermal growth factor receptor|EGFR]]). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an [[Signal transducing adaptor protein|adaptor protein]] ([[GRB2]]), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the [[mitogen-activated protein kinase]] (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the [[MAPK/ERK pathway]]. The MAPK protein is an enzyme, a [[protein kinase]] that can attach [[phosphate]] to target proteins such as the [[transcription factor]] [[C-myc|MYC]] and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.{{citation needed|date=January 2011}}

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the [[hedgehog (cell signaling)|hedgehog protein]] activates different genes, depending on the amount of hedgehog protein present.{{citation needed|date=January 2011}}

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.{{citation needed|date=January 2011}}

A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of a cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control [[Protein biosynthesis|protein synthesis]] by turning certain genes on and off in the nucleus.
<ref>{{cite book|last1=Reece|first1=Jane B.| name-list-style = vanc  |title=Campbell Biology|url= https://archive.org/details/campbellbiologyj00reec |url-access=registration |date=Sep 27, 2010 |publisher=Benjamin Cummings|isbn=978-0-321-55823-7|page=[https://archive.org/details/campbellbiologyj00reec/page/215 215]|edition=9th}}<!--|access-date=11 February 2015--></ref>

In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a [[Dormancy|dormant state]], enhance [[virulence]], defend against [[bacteriophage]]s, etc.<ref name="pmid9671779">{{cite journal | vauthors = Mukamolova GV, Kaprelyants AS, Young DI, Young M, Kell DB | title = A bacterial cytokine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 15 | pages = 8916–21 | date = July 1998 | pmid = 9671779 | pmc = 21177 | doi = 10.1073/pnas.95.15.8916 | bibcode = 1998PNAS...95.8916M | doi-access = free }}</ref> In [[quorum sensing]], which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response.  In this context, the signaling molecules are called [[autoinducer]]s.<ref name=miller>{{cite journal | vauthors = Miller MB, Bassler BL | title = Quorum sensing in bacteria | journal = Annual Review of Microbiology | volume = 55 | issue = 1 | pages = 165–99 | date = 1 October 2001 | pmid = 11544353 | doi = 10.1146/annurev.micro.55.1.165 }}</ref><ref name="pmid15908344">{{cite journal | vauthors = Kaper JB, Sperandio V | title = Bacterial cell-to-cell signaling in the gastrointestinal tract | journal = Infection and Immunity | volume = 73 | issue = 6 | pages = 3197–209 | date = June 2005 | pmid = 15908344 | pmc = 1111840 | doi = 10.1128/IAI.73.6.3197-3209.2005 }}</ref><ref name="pmid16497924">{{cite journal | vauthors = Camilli A, Bassler BL | title = Bacterial small-molecule signaling pathways | journal = Science | volume = 311 | issue = 5764 | pages = 1113–6 | date = February 2006 | pmid = 16497924 | pmc = 2776824 | doi = 10.1126/science.1121357 | bibcode = 2006Sci...311.1113C }}</ref> This signaling mechanism may have been involved in [[evolution]] from unicellular to multicellular organisms.<ref name=miller/><ref name="pmid10343281">{{cite journal | vauthors = Stoka AM | title = Phylogeny and evolution of chemical communication: an endocrine approach | journal = Journal of Molecular Endocrinology | volume = 22 | issue = 3 | pages = 207–25 | date = June 1999 | pmid = 10343281 | doi = 10.1677/jme.0.0220207 | doi-access = free }}</ref> Bacteria also use contact-dependent signaling, notably to limit their growth.<ref name="pmid19246237">{{cite journal | vauthors = Blango MG, Mulvey MA | title = Bacterial landlines: contact-dependent signaling in bacterial populations | journal = Current Opinion in Microbiology | volume = 12 | issue = 2 | pages = 177–81 | date = April 2009 | pmid = 19246237 | pmc = 2668724 | doi = 10.1016/j.mib.2009.01.011 }}</ref>

Signaling molecules used by multicellular organisms are often called [[pheromone]]s. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.<ref>{{cite journal | vauthors = Tirindelli R, Dibattista M, Pifferi S, Menini A | title = From pheromones to behavior | journal = Physiological Reviews | volume = 89 | issue = 3 | pages = 921–56 | date = July 2009 | pmid = 19584317 | doi = 10.1152/physrev.00037.2008 | citeseerx = 10.1.1.460.5566 }}</ref>

===Short-term cellular responses===
{| class="wikitable"

|+ Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses<ref name="Cell biology/Pollard et al">Cell biology/Pollard et al,{{full|date=February 2025}}{{pn|date=February 2025}}</ref><ref name="The Cell/ G.M. Cooper">The Cell/ G.M. Cooper{{full|date=February 2025}}{{pn|date=February 2025}}</ref>

!Receptor Family
!Example of Ligands/ activators (Bracket: receptor for it)
!Example of [[effector (biology)|effectors]]
!Further downstream effects

|-

|Ligand Gated Ion Channels
|[[Acetylcholine]] <br /> (such as [[Nicotinic acetylcholine receptor]]),
|Changes in membrane permeability
|Change in membrane potential

|-

|[[G protein-coupled receptor|Seven Helix Receptor]]
|Light ([[Rhodopsin]]), <br /> [[Dopamine]] ([[Dopamine receptor]]), <br /> [[GABA]] ([[GABA receptor]]), <br /> [[Prostaglandin]] ([[prostaglandin receptor]]) etc.
|Trimeric [[G protein]]
|[[Adenylyl cyclase|Adenylate Cyclase]], <br /> cGMP phosphodiesterase, <br /> [[G protein-gated ion channel|G-protein gated ion channel]], etc.

|-

|[[Two-component regulatory system|Two-component]]
|Diverse activators
|Histidine Kinase
|Response Regulator - flagellar movement, Gene expression

|-

|-

|Membrane Guanylyl Cyclase
|[[Atrial natriuretic peptide]], <br /> Sea urchin egg peptide etc.
|[[Cyclic guanosine monophosphate|cGMP]]
|Regulation of Kinases and channels- Diverse actions

|-

|Cytoplasmic Guanylyl cyclase
|[[Nitric Oxide]] ([[Nitric oxide receptor]])
|[[Cyclic guanosine monophosphate|cGMP]]
|Regulation of cGMP Gated channels, Kinases

|-

|[[Integrins]]
|[[Fibronectins]], other extracellular matrix proteins
|Nonreceptor tyrosine kinase
|Diverse response

|}
{{Clear}}

===Regulating gene activity===
{| class="wikitable"

|+ Brief overview of some signaling pathways (based on receptor families) that control gene activity<ref name="Cell biology/Pollard et al" /><ref name="The Cell/ G.M. Cooper" />

|[[Frizzled]] (special type of 7Helix receptor)
|[[Wnt signaling pathway|Wnt]]
|[[Dishevelled]], axin - APC, GSK3-beta - Beta catenin
|Gene expression

|-

|[[Two-component regulatory system|Two-component]]
|Diverse activators
|Histidine Kinase
|Response Regulator - flagellar movement, Gene expression

|-

|[[Receptor Tyrosine Kinase]]
|[[Insulin]] ([[insulin receptor]]), <br /> [[Epidermal growth factor|EGF]] ([[Epidermal growth factor receptor|EGF receptor]]), <br /> [[Fibroblast growth factor|FGF]]-Alpha, FGF-Beta, etc. ([[Fibroblast growth factor receptor|FGF-receptors]])
|[[Ras protein|Ras]], [[Mitogen-activated protein kinase|MAP-kinases]], [[Phospholipase C|PLC]], [[Phosphoinositide 3-kinase|PI3-Kinase]]
|Gene expression change

|-

|[[Cytokine receptors]]
|Erythropoietin, <br /> [[Growth Hormone]] ([[Growth hormone receptor|Growth Hormone Receptor]]), <br /> [[Interferon gamma|IFN-Gamma]] ([[Interferon-gamma receptor|IFN-Gamma receptor]]) etc.
|[[Janus kinase|JAK kinase]]
|[[STAT protein|STAT transcription factor]] - Gene expression

|-

|Tyrosine kinase Linked- receptors
|MHC-peptide complex - TCR, Antigens - BCR
|Cytoplasmic Tyrosine Kinase
|Gene expression

|-

|[[Receptor protein serine/threonine kinase|Receptor Serine/Threonine Kinase]]
|[[Activin]] ([[activin receptor]]), <br /> [[Inhibin]], <br /> [[Bone morphogenetic protein|Bone-morphogenetic protein]] ([[Bone morphogenetic protein receptor|BMP Receptor]]), <br /> [[Transforming growth factor beta|TGF-beta]]
|[[SMAD (protein)|Smad]] transcription factors
|Control of gene expression

|-

|Sphingomyelinase linked receptors
|[[Interleukin-1 family|IL-1]] ([[Interleukin-1 receptor|IL-1 receptor]]), <br /> [[Tumor necrosis factor|TNF]] ([[TNF receptor superfamily|TNF-receptors]])
|Ceramide activated kinases
|Gene expression

|-

|Cytoplasmic Steroid receptors
|[[Steroid hormones]], <br /> [[Thyroid hormone]]s, <br /> [[Retinoic acid]] etc.
|Work as/ interact with transcription factors
|Gene expression

|}{{Clear}}

[[File:signal transduction pathways.png|thumb|500px|right|Signal transduction pathways that lead to a cellular response]]
{{Clear}}

====Notch signaling pathway====
[[File:Notchccr.svg|thumb|right|''[[Notch signaling pathway|Notch]]''-mediated juxtacrine signal between adjacent cells]]
[[Notch signaling pathway|Notch]] is a cell surface protein that functions as a receptor. Animals have a small set of [[gene]]s that [[Codon|code]] for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that [[Gene expression|express]] Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, [[neurotransmitter]]s, [[cytokine]]s, and [[growth factors]], in general called [[ligand (biochemistry)|receptor ligands]]. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication.<ref>{{cite book |last1=Cooper |first1=Geoffrey M. |title=The Cell: A Molecular Approach |edition=2nd |date=2000 |publisher=Sinauer Associates |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK9866/ |chapter=Functions of Cell Surface Receptors }}</ref> Notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, [[estrogen]] is a [[hydrophobic]] molecule that can pass through the [[lipid bilayer]] of the [[cell membrane|membrane]]s. As part of the [[endocrine system]], intracellular [[estrogen receptor]]s from a variety of [[Cell type|cell types]] can be activated by estrogen produced in the ovaries.{{citation needed|date=September 2023}}

In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a [[protease]]. Part of the Notch protein is released from the cell surface membrane and takes part in [[gene regulation]]. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types.<ref>{{cite journal | vauthors = Ferrell JE, Machleder EM | title = The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes | journal = Science | volume = 280 | issue = 5365 | pages = 895–8 | date = May 1998 | pmid = 9572732 | doi = 10.1126/science.280.5365.895 | bibcode = 1998Sci...280..895F }}</ref><ref>{{cite journal | vauthors = Slavov N, Carey J, Linse S | title = Calmodulin transduces Ca2+ oscillations into differential regulation of its target proteins | journal = ACS Chemical Neuroscience | volume = 4 | issue = 4 | pages = 601–12 | date = April 2013 | pmid = 23384199 | pmc = 3629746 | doi = 10.1021/cn300218d }}</ref> Emerging methods for [[Single-cell analysis|single-cell mass-spectrometry analysis]] promise to enable studying signal transduction with single-cell resolution.<ref>{{cite journal | vauthors = Slavov N | title = Unpicking the proteome in single cells | journal = Science | volume = 367 | issue = 6477 | pages = 512–513 | date = January 2020 | pmid = 32001644 | doi = 10.1126/science.aaz6695 | pmc = 7029782 | bibcode = 2020Sci...367..512S }}</ref>

In [[notch signaling]], direct contact between cells allows for precise control of cell [[differentiation (cellular)|differentiation]] during [[embryonic development]]. In the worm ''[[Caenorhabditis elegans]]'', two cells of the developing [[gonad]] each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch [[#Receptors|receptor]] on the adjacent cell. This activates a [[feedback loop]] or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a [[stem cell]].<ref name="Greenwald1998">{{cite journal | vauthors = Greenwald I | title = LIN-12/Notch signaling: lessons from worms and flies | journal = Genes & Development | volume = 12 | issue = 12 | pages = 1751–62 | date = June 1998 | pmid = 9637676 | doi = 10.1101/gad.12.12.1751 | doi-access = free }}</ref>

==See also==
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-->
{{colbegin}}
* [[Scaffold protein]]
* [[Biosemiotics]]
* [[Molecular cellular cognition]]
* [[Crosstalk (biology)]]
* [[Bacterial outer membrane vesicles]]
* [[Membrane vesicle trafficking]]
* [[Host–pathogen interaction]]
* [[Retinoic acid]]
* [[JAK-STAT signaling pathway]]
* [[Imd pathway]]
* [[Signal peptide|Localisation signal]]
* [[Oscillation (cell signaling)|Oscillation]]
* [[Protein dynamics]]
* [[Systems biology]]
* [[Lipid signaling]]
* [[Redox signaling]]
* [[Signaling cascade]]
* [[Cell Signaling Technology]] – an antibody development and production company
* [[Netpath]] – a curated resource of signal transduction pathways in humans
* [[Synthetic Biology Open Language]]
* [[Nanoscale networking]] – leveraging biological signaling to construct ad hoc in vivo communication networks
* [[Soliton model in neuroscience]] – physical communication via sound waves in membranes
* [[Temporal feedback]]
{{colend}}

==References==
{{Reflist|30em}}

==Further reading==
{{refbegin}}
* "The Inside Story of Cell Communication". ''learn.genetics.utah.edu''. Retrieved 2018-10-20.
* "When Cell Communication Goes Wrong". ''learn.genetics.utah.edu''. Retrieved 2018-10-24.
{{refend}}

==External links==
* [https://web.archive.org/web/20070715233022/http://pid.nci.nih.gov/ NCI-Nature Pathway Interaction Database]: authoritative information about signaling pathways in human cells.
* {{MeshName|Intercellular+Signaling+Peptides+and+Proteins}}
* {{MeshName|Cell+Communication}}
* [https://www.signalingpathways.org Signaling Pathways Project]: cell signaling hypothesis generation knowledgebase constructed using biocurated archived transcriptomic and ChIP-Seq datasets

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[[Category:Cell signaling| ]]
[[Category:Cell biology]]
[[Category:Cell communication]]
[[Category:Systems biology]]
[[Category:Human female endocrine system]]