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Cell signaling
Cell signaling
Cell signaling
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In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryotes. Typically, the signaling process involves three components: the first messenger (the ligand), the receptor, and the signal itself.[1]

In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including ions (e.g. Na+, K+, Ca2+, 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,[dubious – discuss]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.[2] Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell.[3] Juxtacrine signaling occurs between physically adjacent cells.[4] Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.[5]

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, organelles, and 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.

Diagram of G-protein coupled reception

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 receptors are multimeric proteins embedded within the plasma membrane. These receptors have extracellular, trans-membrane and intracellular 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 receptors 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 receptors 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 downstream effects of these signaling pathways may include additional enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.

Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.

Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of development, tissue repair, immunity, and homeostasis. Errors in signaling interactions may cause diseases such as cancer, autoimmunity, and diabetes.

Taxonomic range

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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 produces light when the population is dense enough.[6] 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.[7]

In slime molds, 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 glorin.[8]

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.[9] Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule.[10] Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.

Extracellular signal

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Synthesis and release

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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: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or 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. glucocorticoids, thyroid hormones, 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.[10] 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.[11] 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: nitric oxide and carbon monoxide.[12]

Exocytosis

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Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins 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 substances important to them are large 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 porosomes. 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.[13]

In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.[citation needed]

Types of Cell Signaling

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Autocrine

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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.[14] This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

Intracrine

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In 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.[15]

Juxtacrine

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Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:

This image displays the different types of cell signaling
  1. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
  2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
  3. 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 factors, 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,[16] and in the adult brain.[17]

Paracrine

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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.[18] Neurotransmitters 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 neurons to function as a neurotransmitter within the brain.[19] Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.[20]

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 organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development.[21] The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.

Endocrine

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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 signals are called hormones. Hormones are produced by endocrine cells and they travel through the 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 glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.

Receptors

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Main article: Receptor (biochemistry)
Transmembrane receptor working principle

Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (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 receptors, 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 receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. In many mammals, early embryo cells exchange signals with cells of the uterus.[22] In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells.[23] For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) 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.[24]

Cell surface receptors

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See also: Ligand (biochemistry) and 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.[25] These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. There are three major types: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors.

Ion channel linked receptors

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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 Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.[26][27][28]

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 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, 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 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 synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

G protein–coupled receptors

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A G Protein-coupled receptor within the plasma membrane

G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, 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.[29] 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 agonists although a spontaneous auto-activation of an empty receptor can also be observed.[29]

G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates,[30] and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway.[31] 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 GDP bound to the G protein for a 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 (Gαs, Gαi/o, Gαq/11, Gα12/13).[32]: 1160 

G protein-coupled receptors are an important drug target and approximately 34%[33] 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 2018.[33] 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.[29]

Enzyme-linked receptors

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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, causes enzymatic activity on the intracellular side.[34] Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions.[35]

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] Examples of the enzymatic activity include:

Intracellular receptors

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Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to organelles or membranes. For example, the presence of nuclear and mitochondrial receptors is well documented.[37] 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.[38] Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of DNA binding proteins. Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of gene expression.[citation needed]

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A)[39] and 3-ketosteroids (group NR3C).[40] In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

Mechanisms of Receptor Down-Regulation

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Further information: Downregulation and upregulation

Receptor mediated endocytosis is a common way of turning receptors "off". Endocytic down regulation is regarded as a means for reducing receptor signaling.[41] 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.[42]

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.[43]

Signal transduction pathways

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Further information: Signal transduction and 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 amplification 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 organisms.[11]

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 GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABAA receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABAA receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. 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 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.[44]

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 interactions 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 divide. Several of these receptors are kinases 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 EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an 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 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]

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.[citation needed]

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]

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 cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus. [45]

In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc.[46] 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 autoinducers.[47][48][49] This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms.[47][50] Bacteria also use contact-dependent signaling, notably to limit their growth.[51]

Signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.[52]

Short-term cellular responses

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Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses[53][54]
Receptor Family Example of Ligands/ activators (Bracket: receptor for it) Example of effectors Further downstream effects
Ligand Gated Ion Channels Acetylcholine
(such as Nicotinic acetylcholine receptor), 		Changes in membrane permeability Change in membrane potential
Seven Helix Receptor Light (Rhodopsin),
Dopamine (Dopamine receptor),
GABA (GABA receptor),
Prostaglandin (prostaglandin receptor) etc. 		Trimeric G protein Adenylate Cyclase,
cGMP phosphodiesterase,
G-protein gated ion channel, etc.
Two-component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Membrane Guanylyl Cyclase Atrial natriuretic peptide,
Sea urchin egg peptide etc. 		cGMP Regulation of Kinases and channels- Diverse actions
Cytoplasmic Guanylyl cyclase Nitric Oxide (Nitric oxide receptor) cGMP Regulation of cGMP Gated channels, Kinases
Integrins Fibronectins, other extracellular matrix proteins Nonreceptor tyrosine kinase Diverse response

Regulating gene activity

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Brief overview of some signaling pathways (based on receptor families) that control gene activity[53][54]
Frizzled (special type of 7Helix receptor) Wnt Dishevelled, axin - APC, GSK3-beta - Beta catenin Gene expression
Two-component Diverse activators Histidine Kinase Response Regulator - flagellar movement, Gene expression
Receptor Tyrosine Kinase Insulin (insulin receptor),
EGF (EGF receptor),
FGF-Alpha, FGF-Beta, etc. (FGF-receptors) 		Ras, MAP-kinases, PLC, PI3-Kinase Gene expression change
Cytokine receptors Erythropoietin,
Growth Hormone (Growth Hormone Receptor),
IFN-Gamma (IFN-Gamma receptor) etc. 		JAK kinase STAT transcription factor - Gene expression
Tyrosine kinase Linked- receptors MHC-peptide complex - TCR, Antigens - BCR Cytoplasmic Tyrosine Kinase Gene expression
Receptor Serine/Threonine Kinase Activin (activin receptor),
Inhibin,
Bone-morphogenetic protein (BMP Receptor),
TGF-beta 		Smad transcription factors Control of gene expression
Sphingomyelinase linked receptors IL-1 (IL-1 receptor),
TNF (TNF-receptors) 		Ceramide activated kinases Gene expression
Cytoplasmic Steroid receptors Steroid hormones,
Thyroid hormones,
Retinoic acid etc. 		Work as/ interact with transcription factors Gene expression
Signal transduction pathways that lead to a cellular response

Notch signaling pathway

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Notch-mediated juxtacrine signal between adjacent cells

Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called 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.[55] 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 membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.[citation needed]

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.[56][57] Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.[58]

In notch signaling, direct contact between cells allows for precise control of cell 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 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.[59]

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cell signaling

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Cell signaling, also known as , is the fundamental process by which cells detect and respond to external stimuli from their environment or neighboring cells, enabling coordinated regulation of cellular activities such as , growth, division, differentiation, and death. This communication is vital for all organisms, from single-celled that sense nutrient gradients to complex multicellular systems where it orchestrates development, , and immune responses. In multicellular organisms, cell signaling occurs through diverse modes categorized by the distance and specificity of . Endocrine signaling involves hormones like insulin traveling through the bloodstream to distant target cells, regulating processes such as glucose across the body. employs molecules like growth factors that act locally on nearby cells, facilitating short-range coordination such as in or synaptic transmission. allows cells to respond to their own secreted signals, often playing roles in self-sustained proliferation, as seen with certain cancer cells producing their own growth factors. Additional modes include direct contact-dependent signaling via cell surface proteins and synaptic signaling in neurons using neurotransmitters like . Signaling molecules encompass a wide array, including hydrophilic peptides and proteins (e.g., ), hydrophobic (e.g., ), gases like , and lipids such as prostaglandins, each adapted to diffuse or bind specific receptors. Receptors, which bind these with high affinity (often at concentrations below 10^{-8} M), are primarily transmembrane proteins on the cell surface for water-soluble signals or intracellular for lipophilic ones like steroid hormones that directly influence . Upon ligand binding, receptors initiate intracellular pathways, frequently involving second messengers such as cyclic AMP or calcium ions, which amplify the signal and activate cascades of protein kinases to elicit diverse cellular responses. Dysregulation of cell signaling pathways underlies numerous diseases, including cancer—where mutations in signaling components like receptor tyrosine kinases promote uncontrolled growth—and , highlighting the therapeutic potential of targeting these pathways. Ongoing research continues to uncover intricate networks, such as those integrating multiple signals for context-specific outcomes, underscoring cell signaling's role as a cornerstone of cellular and organismal .

Overview

Definition and scope

Cell signaling is the process by which cells detect and respond to internal and external molecular cues, enabling communication between cells and coordination of physiological functions across organisms. This involves the transmission of signals from a sending cell or the environment to a receiving cell, typically through ligands—diverse molecules such as hormones, neurotransmitters, or growth factors—that bind to specific receptors on or within the target cell, triggering intracellular changes that alter cellular . The scope of cell signaling encompasses both unicellular and multicellular organisms, where it facilitates responses to stimuli like nutrients, pathogens, or mechanical stress, ensuring survival, growth, and adaptation without requiring direct physical contact. At its core, cell signaling relies on four key components: ligands, which serve as the primary signaling molecules; receptors, which are specialized proteins that recognize and bind ligands with high affinity; second messengers, such as cyclic AMP (cAMP), inositol (IP₃), or calcium ions (Ca²⁺), that propagate and amplify the signal inside the cell; and effectors, including enzymes like kinases or transcription factors, that execute the final cellular outcomes. These elements form integrated networks that allow precise regulation, where even low concentrations of extracellular signals can elicit robust intracellular responses through cascading amplification. The fundamental process of cell signaling unfolds in three stages: reception, where binding induces a conformational change in the receptor; transduction, involving relay mechanisms like enzymatic activations or second messenger that convert the external signal into intracellular events; and response, where the amplified signal drives specific outcomes such as cytoskeletal reorganization or changes. This streamlined pathway ensures efficient information transfer while minimizing noise, allowing cells to integrate multiple signals for context-dependent decisions. Cell signaling is indispensable for enabling cell differentiation, proliferation, apoptosis, and environmental adaptation, playing pivotal roles in embryonic development, activation, and tissue repair processes that restore after injury. Dysregulation of these pathways underlies diseases like cancer and , highlighting their broad biological impact. Historically, the field built on Earl W. Sutherland's pioneering 1950s experiments demonstrating cAMP as the first intracellular second messenger in hormone action, for which he received the 1971 Nobel Prize in or ; the modern term "cell signaling" emerged in the late , formalizing concepts from the 1970s era of research.

Evolutionary and taxonomic aspects

Cell signaling mechanisms originated in prokaryotes, with early forms evident in bacterial quorum sensing systems that utilize autoinducers to coordinate population-level behaviors such as biofilm formation and virulence factor expression. These pathways, which rely on diffusible signaling molecules to detect cell density, represent an ancient adaptation for environmental sensing and survival, predating the divergence of major bacterial lineages. In parallel, two-component systems in bacteria, involving histidine kinases and response regulators, emerged as a foundational mode of signal transduction for detecting nutrients, toxins, and osmotic changes, enabling rapid adaptive responses. These prokaryotic signaling strategies are conserved and expanded in eukaryotes, from unicellular organisms like to complex multicellular animals, reflecting a shared evolutionary heritage. Core elements, such as receptor-ligand binding and cascades, trace back to prokaryotic ancestors and have been reiterated across domains. For instance, two-component systems in prokaryotes and (MAPK) cascades in eukaryotes exemplify modular signal amplification in diverse contexts. In eukaryotes, these mechanisms underpin developmental processes, with expansions in metazoans allowing for tissue-specific coordination, as seen in the integration of signaling modules for . Cell signaling is ubiquitous across all domains of life, manifesting in through chemotaxis pathways that direct motility toward favorable conditions via two-component-like systems distinct from bacterial homologs yet functionally analogous. In , two-component systems dominate, facilitating environmental adaptation, while in Eukarya, G-protein-coupled receptors (GPCRs) are prevalent in for hormone perception, in fungi for nutrient and stress responses, and in animals for sensory and intercellular communication. Prokaryotic signaling primarily supports survival strategies like nutrient sensing and population coordination, whereas eukaryotic adaptations emphasize developmental patterning, exemplified by the Wnt pathway's role in axis formation and tissue morphogenesis in animals. Horizontal gene transfer has significantly contributed to the dissemination of signaling genes across taxa, particularly two-component systems that originated in and spread to and eukaryotes, enhancing adaptive versatility in recipient organisms. This process underscores the dynamic evolution of signaling networks, allowing prokaryotes to acquire eukaryotic-like modules and vice versa, thereby blurring strict domain boundaries in architecture.

Signaling Molecules

Extracellular signals

Extracellular signals are molecules produced by cells and released into the extracellular environment to communicate with other cells, enabling coordinated responses in multicellular organisms. These signals traverse the , interstitial fluids, or bloodstream, with their range determined by factors such as molecular size, solubility, and degradation rates—local signals like growth factors act over short distances (micrometers to millimeters), while systemic ones like hormones can travel throughout the body. The synthesis and release of these signals are tightly regulated to maintain physiological , and their chemical diversity allows for specific interactions in various biological contexts. Extracellular signals are broadly classified by their chemical nature and function. Peptide and protein signals, such as hormones (e.g., insulin), cytokines (e.g., ), and growth factors (e.g., ), are hydrophilic and typically water-soluble, requiring vesicular transport for release. Small-molecule neurotransmitters, such as , are also hydrophilic but not peptide-based. In contrast, steroid hormones (e.g., ) are lipophilic, derived from , and diffuse across membranes. Lipid-derived signals, such as prostaglandins and other eicosanoids, are hydrophobic molecules synthesized from released from membrane phospholipids via enzymes like (COX). Gaseous signals like (NO) are small, non-polar molecules produced on demand without storage. This classification influences their stability and mode of action, with peptides often having short half-lives (minutes) due to enzymatic degradation, while steroids persist longer (hours). Synthesis of extracellular signals occurs in specialized cellular compartments. Peptide signals are transcribed from genes, translated in the rough (ER), and processed through glycosylation and cleavage in the Golgi apparatus before packaging into secretory vesicles. Steroid signals are synthesized in the smooth ER and mitochondria of endocrine cells, involving enzymatic conversions of cholesterol via enzymes. Lipid-derived signals like prostaglandins are produced in the and membranes through the pathway. Gasotransmitters like NO are generated enzymatically by () in the , using L-arginine as a substrate, with production regulated by calcium-calmodulin binding. Transcriptional control, such as via nuclear receptors, and post-translational modifications like ensure precise regulation of signal production in response to cellular cues. Release mechanisms primarily involve exocytosis, where signaling molecules in vesicles fuse with the plasma membrane in a calcium-dependent manner, triggered by depolarization or receptor activation. For instance, insulin is released from pancreatic beta cells via regulated exocytosis following glucose-stimulated insulin secretion. Small lipophilic molecules like steroids, lipids, and gases such as NO are released by simple diffusion across the lipid bilayer, bypassing vesicular pathways. Unconventional secretion, including direct translocation or extracellular vesicle release, applies to certain cytokines and growth factors that lack signal peptides. Concentration gradients form post-release, with half-lives varying—acetylcholine is rapidly hydrolyzed by acetylcholinesterase (milliseconds), ensuring transient synaptic signaling, while insulin circulates with a half-life of about 5-10 minutes. These processes allow extracellular signals to mediate both local autocrine/paracrine effects and distant endocrine communication.

Intracellular signals

Intracellular signals, commonly known as second messengers, are small molecules or ions produced within the cell in response to the activation of cell surface receptors by extracellular ligands. These include (cAMP), inositol 1,4,5-trisphosphate (IP₃), diacylglycerol (DAG), and calcium ions (Ca²⁺), which serve to transduce and amplify the initial signal inside the cell. The generation of these second messengers typically occurs through receptor-coupled enzymes that catalyze rapid biochemical reactions. For instance, in (GPCR) pathways, activation of converts ATP to cAMP, while (PLC) hydrolyzes (PIP₂) in the plasma membrane to produce IP₃ and DAG. Enzymatic cascades further amplify these signals, allowing a single receptor activation to generate thousands of second messenger molecules. Ca²⁺, often mobilized from intracellular stores like the in response to IP₃ binding to its receptors, also acts as a key second messenger. These molecules relay information from the plasma membrane to intracellular targets, such as enzymes in the or transcription factors in the nucleus, enabling diverse cellular responses. Spatial and temporal control is achieved through gradients, binding to proteins, or localized production, which prevents indiscriminate signaling. For example, cAMP in GPCR pathways binds to and activates (PKA), leading to of downstream targets that regulate processes like glycogen breakdown. Similarly, Ca²⁺ waves propagate across cells to trigger muscle contraction in cardiomyocytes or synaptic vesicle secretion in neurons. Signal termination is critical for specificity; degradation mechanisms, such as cAMP phosphodiesterases converting cAMP to AMP, rapidly lower concentrations, often restoring levels from stimulated micromolar ranges (e.g., 1–10 μM for Ca²⁺ or cAMP peaks) back to basal nanomolar states.

Modes of Intercellular Communication

Autocrine and paracrine signaling

refers to a mode of cellular communication in which a cell produces a signaling molecule, or , that binds to receptors on its own surface, thereby influencing its own without involving other cells. This self-regulatory mechanism allows cells to fine-tune their responses to internal or environmental cues, often amplifying or sustaining specific physiological processes. In contrast, involves the release of ligands that diffuse through the to act on neighboring cells within a localized area, enabling coordinated responses among adjacent cells without systemic spread. Both forms represent short-range intercellular communication, distinguished from longer-range endocrine signaling by their reliance on over limited distances. In , the ligand's action on the producing cell can create feedback loops that promote cell survival, proliferation, or differentiation. A prominent example is the role of transforming growth factor-β (TGF-β) in cancer cells, where autocrine secretion of TGF-β binds to receptors on the same tumor cells, driving epithelial-to-mesenchymal transition and enhancing invasiveness. This autocrine loop sustains tumor growth by maintaining a pro-proliferative state, as observed in various carcinomas where TGF-β expression correlates with aggressive phenotypes. Such loops are particularly implicated in pathological conditions, where dysregulated autocrine signaling can perpetuate uncontrolled and resistance to . Paracrine signaling facilitates rapid, localized interactions essential for tissue homeostasis and response to . For instance, in , platelets release (PDGF) that diffuses to nearby fibroblasts and endothelial cells, stimulating proliferation and to promote tissue repair. Similarly, in immune , T cells secrete interleukin-2 (IL-2), which acts paracrine on adjacent lymphocytes to enhance proliferation and effector functions during inflammatory responses. Neurotransmitters at synapses exemplify in the , where molecules like glutamate diffuse across the synaptic cleft to activate receptors on postsynaptic cells, enabling swift . The mechanisms underlying both autocrine and paracrine signaling are governed by diffusion of soluble ligands through the , limiting their effective range to nanometers (e.g., synaptic clefts of ~20-40 nm) up to a few millimeters in denser tissues. This short-range propagation ensures rapid onset of responses, often within seconds to minutes, followed by quick decay due to ligand degradation, uptake, or dilution, preventing unintended widespread effects. Ligand-receptor binding initiates downstream events via cell surface or intracellular receptors, though the core distinction lies in the spatial confinement of these interactions. In pathological contexts, such as tumor microenvironments, autocrine loops involving growth factors like TGF-β can drive autonomous cancer progression, underscoring their role in disease while highlighting their separation from distant endocrine modes by proximity.

Endocrine and juxtacrine signaling

Endocrine signaling involves the secretion of hormones by specialized endocrine cells, which are then transported through the bloodstream to act on distant target cells throughout the body. This mode of communication enables systemic regulation of physiological processes, such as , growth, and stress responses. For instance, adrenaline (epinephrine), released from the adrenal glands, circulates via the blood to bind β-adrenergic receptors on target cells like those in the heart and lungs, triggering the by increasing heart rate and bronchodilation. Similarly, , produced by the gland, travel through the circulation to regulate by binding to nuclear receptors in various tissues, thereby influencing energy expenditure and . In contrast, juxtacrine signaling requires direct physical contact between cells, typically mediated by membrane-bound on one cell interacting with receptors on an adjacent cell. This contact-dependent mechanism ensures highly localized and precise signal transmission, often crucial for developmental processes like and tissue patterning. A prominent example is the Notch-Delta pathway, where the membrane-bound ligand Delta on a signaling cell binds the Notch receptor on a neighboring cell, leading to proteolytic cleavage of Notch and release of its intracellular domain to modulate for decisions in cell differentiation during embryogenesis. Another key instance is Ephrin-Eph signaling, where membrane-anchored ephrins bind Eph receptors on adjacent cells to provide bidirectional cues that guide in the , preventing misguided projections and establishing topographic maps. The mechanisms underlying endocrine signaling rely on the for hormone distribution, with target specificity achieved through selective binding to cell surface or intracellular receptors that recognize particular . often exhibit longer half-lives in the blood—ranging from minutes for catecholamines like adrenaline to hours or days for and —allowing sustained effects but potentially lower spatial specificity compared to local signals like paracrine . Juxtacrine signaling, however, utilizes molecules and transmembrane interactions for signal transfer without diffusible mediators, enabling rapid, high-fidelity patterning in tissues where precise cell-cell coordination is essential, such as in boundary formation during development. This contact-based nature confers greater specificity and immediacy, contrasting with the broader reach of endocrine signals.

Receptors

Cell surface receptors

Cell surface receptors are membrane proteins embedded in the plasma that detect extracellular signaling molecules, primarily hydrophilic ligands unable to cross the , and transduce these signals into intracellular responses. These receptors typically consist of an extracellular ligand-binding domain that recognizes specific signals, a hydrophobic that spans the bilayer, and an intracellular signaling domain that interacts with downstream effectors to propagate the signal. Unlike intracellular receptors, which bind lipophilic ligands in the or nucleus, cell surface receptors serve as the primary interface for cell-cell communication via water-soluble messengers. The major classes of cell surface receptors are distinguished by their structure and mechanism of action. Ion channel-linked receptors, also known as ligand-gated ion channels, form pores that open or close upon binding, enabling rapid changes in through ion flux such as Na⁺, K⁺, Ca²⁺, or Cl⁻. A representative example is the , which binds to allow sodium influx, facilitating synaptic transmission in neuromuscular junctions. G protein-coupled receptors (GPCRs) represent the largest superfamily, comprising approximately 800 genes in the and accounting for about 4% of protein-coding genes. These receptors feature seven α-helical transmembrane domains that form a barrel-like structure, with an extracellular for ligand recognition and an intracellular that couples to heterotrimeric G proteins, activating pathways involving second messengers like cyclic AMP (cAMP) or inositol trisphosphate (). GPCRs detect diverse stimuli, including light through in rod cells of the and odors via olfactory receptors in nasal . Enzyme-linked receptors contain or associate with enzymatic domains that catalyze or other modifications upon . Receptor tyrosine kinases (RTKs), a key subclass, dimerize upon ligand binding, leading to autophosphorylation on intracellular residues and recruitment of signaling proteins. The (EGFR), for instance, binds (EGF) to initiate cascades promoting and survival. Ligand binding to cell surface receptors exhibits high specificity, often following the lock-and-key model where the precisely fits a preformed binding pocket, or the induced fit model involving conformational changes in the receptor to optimize interactions. Binding affinity is quantified by the (K_d), typically in the nanomolar (nM) range (e.g., 0.3–0.5 nM for certain receptor-ligand pairs), ensuring sensitive detection of low-concentration signals. Mutations in receptor genes underlie numerous diseases, including from insulin receptor defects and certain cancers from EGFR dysregulation, highlighting their clinical significance.

Intracellular receptors

Intracellular receptors, primarily comprising the superfamily, are ligand-activated transcription factors located within the cell, either in the or nucleus, that respond to lipophilic signaling molecules capable of crossing the plasma membrane. These receptors include receptors, such as the (ER), (AR), glucocorticoid receptor (GR), progesterone receptor (PR), and mineralocorticoid receptor (MR); non-steroid receptors like thyroid hormone receptor (TR), retinoic acid receptor (RAR), vitamin D receptor (VDR), and peroxisome proliferator-activated receptor (PPAR); and orphan receptors, such as the testicular receptor, for which endogenous ligands remain unidentified. In humans, approximately 48 s have been identified, reflecting their diverse roles in regulating cellular processes like and development. The mechanism of action for these receptors involves the passive diffusion of lipophilic ligands—such as steroids, thyroid hormones, retinoic acid, and vitamin D—across the lipid bilayer of the cell membrane. Upon entering the cell, the ligand binds to the receptor, inducing a conformational change that often releases inhibitory chaperone proteins like heat shock proteins from cytosolic receptors (e.g., GR), exposing a nuclear localization signal that facilitates translocation to the nucleus. The ligand-receptor complex then binds to specific DNA sequences known as hormone response elements (HREs) as homodimers, heterodimers, or monomers, recruiting co-activators or co-repressors to modulate target gene transcription, thereby directly influencing gene expression without intermediary second messengers. Structurally, nuclear receptors share a conserved modular , including an N-terminal domain (NTD) for , a central (DBD) featuring two motifs that recognize HREs, a flexible region containing the nuclear localization signal, and a C-terminal -binding domain (LBD) with a hydrophobic pocket for accommodation and an function-2 (AF-2) that interacts with co-activators or co-repressors to regulate transcriptional activity. These structural elements enable precise specificity and DNA targeting, with co-regulators fine-tuning the receptor's repressive or activating effects on . A prominent example is the (GR), which, upon binding glucocorticoids, translocates to the nucleus and inhibits pro-inflammatory genes by interfering with transcription factors like , thereby suppressing inflammation. Another key instance involves (RXR) heterodimers, such as RXR-PPAR or RXR-LXR complexes, which regulate by activating genes involved in oxidation, efflux, and in the liver. Evolutionarily, nuclear receptors trace back to ancient lipid sensors that emerged around 600 million years ago in bilaterian ancestors, initially functioning as promiscuous detectors of and sterols before diversifying into specialized ligand-responsive transcription factors.

Signal Transduction Pathways

Initiation and amplification

Cell signaling begins with the binding of an extracellular to a specific receptor, which induces a conformational change in the receptor protein, thereby activating downstream effectors. This initial event translates the extracellular signal into an intracellular response, often involving the recruitment and activation of adapter proteins or enzymes that propagate the signal. For instance, in G protein-coupled receptors (GPCRs), ligand binding stabilizes an active receptor conformation that facilitates the interaction with heterotrimeric s, promoting the release of (GDP) from the Gα subunit and its exchange for (GTP). This GDP-GTP exchange dissociates the G protein into active Gα-GTP and Gβγ subunits, each capable of modulating effector enzymes. Signal amplification occurs through multistep enzymatic cascades and the generation of second messengers, allowing a single activated receptor to elicit a robust cellular response. In these cascades, each activated molecule can catalyze the activation of numerous downstream targets, exponentially increasing the signal strength. For example, activated Gαs stimulates to produce hundreds of (cAMP) molecules per second, which in turn activate multiple (PKA) holoenzymes; each PKA can phosphorylate dozens of substrates, further propagating the signal. Similarly, in the (PLC) pathway, activated PLC hydrolyzes (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), with each enzyme molecule generating multiple second messengers that mobilize intracellular calcium and activate (PKC), respectively. Phosphorylation-dephosphorylation cycles contribute to this amplification by enabling ultrasensitive switches, where kinase-phosphatase pairs convert low-level inputs into sharp, all-or-nothing outputs through mechanisms like substrate sequestration and multistep binding, achieving Hill coefficients up to n+1 (where n is the number of phosphorylation sites). Second messengers such as cAMP and IP₃ diffuse rapidly within the , spreading the signal to distal effectors and enhancing amplification. To ensure specificity and prevent crosstalk between pathways, amplification is spatially regulated by scaffold proteins that organize signaling components into localized complexes. These scaffolds tether receptors, kinases, and second messengers, confining signals to microdomains and limiting diffusion-based interference; for example, A-kinase anchoring proteins (AKAPs) localize PKA near in the cAMP pathway. Overall, such mechanisms allow cells to detect and respond effectively to trace concentrations, with amplification ratios potentially exceeding 10⁴ in kinase cascades like MAPK, though exact gains vary by pathway.

Major signaling cascades

Cell signaling pathways often converge on a set of conserved cascades that transduce extracellular cues into intracellular responses, enabling cells to coordinate processes like growth, differentiation, and . These major signaling cascades, including the cAMP-PKA, MAPK/ERK, PI3K-Akt, Notch, Wnt, and TGF-β pathways, exhibit modular architectures where receptor activation triggers sequential enzymatic activations leading to effector modulation. Other prominent cascades include the JAK-STAT pathway, activated by receptors to promote immune responses and hematopoiesis via STAT transcription factors, and the pathway, which regulates and cell through IκB degradation and nuclear translocation of NF-κB. While amplification mechanisms, such as second messenger production, enhance signal strength within these cascades, their specificity arises from scaffold proteins and compartmentalization. The cAMP-PKA pathway is activated by G protein-coupled receptors (GPCRs) coupled to stimulatory G proteins (Gs), which upon ligand binding stimulate to produce cyclic AMP (cAMP) from ATP. Elevated cAMP levels activate (PKA) by binding to its regulatory subunits, releasing catalytic subunits that phosphorylate diverse targets, including the transcription factor CREB to regulate . This pathway is pivotal in responses to hormones like adrenaline, influencing and activity. The MAPK/ERK pathway, often initiated by receptor tyrosine kinases (RTKs), propagates signals through a kinase cascade: ligand-bound RTKs recruit and activate , which in turn activates , leading to sequential and activation of MEK and then ERK. Activated ERK translocates to the nucleus to phosphorylate transcription factors, promoting and differentiation in response to growth factors like EGF. Non-canonical branches, such as the JNK pathway, diverge from this core to handle stress signals, where JNK activation occurs via MAP3K like ASK1 in response to UV or cytokines. The PI3K-Akt pathway is triggered by RTKs or GPCRs, recruiting (PI3K) to the membrane, where it phosphorylates PIP2 to generate PIP3, a second messenger that recruits and activates Akt kinase via PDK1 phosphorylation. Akt then phosphorylates downstream effectors like , regulating cell survival, metabolism, and protein synthesis; dysregulation, such as PTEN mutations that inactivate the PIP3 , hyperactivates this pathway and drives oncogenesis in cancers like . The Notch pathway operates via juxtacrine signaling, where binding on an adjacent cell induces sequential proteolytic cleavages of the Notch receptor by metalloproteases and γ-secretase, releasing the intracellular domain (NICD) that translocates to the nucleus to co-activate transcription factors like CSL, influencing developmental decisions such as cell fate binary choices. Recent studies highlight Notch's ongoing role in maintenance, including asymmetric division in intestinal stem cells and regeneration in muscle satellite cells. Other prominent cascades include the Wnt pathway, where Wnt ligands bind receptors to inhibit the β-catenin destruction complex (APC/Axin/GSK3/CK1), stabilizing β-catenin for nuclear translocation and TCF/LEF-mediated transcription of genes involved in embryogenesis and tissue . The TGF-β pathway, activated by TGF-β family ligands binding type I/II serine/threonine kinase receptors, leads to phosphorylation of receptor-regulated SMADs (R-SMADs) that complex with SMAD4 to enter the nucleus and regulate transcription of extracellular matrix genes critical for . These cascades do not function in isolation; cross-talk integrates multiple inputs, as seen in the convergence of MAPK and PI3K pathways on shared effectors like FoxO transcription factors to determine cell fate outcomes in proliferation versus decisions. Computational models now simulate these dynamics, incorporating kinetic parameters to predict pathway behaviors under varying stimuli and reveal emergent properties like . Recent advances as of 2025 include AI-driven modeling of pathway cross-talk and novel targeted therapies for diseases like cancer.

Cellular Responses

Immediate and short-term effects

Immediate and short-term effects of cell signaling encompass rapid cellular responses that occur without involving changes in , typically manifesting within seconds to minutes through alterations in fluxes, metabolic activities, and cytoskeletal dynamics. These effects enable quick adaptations to environmental cues, such as release or binding, by directly modulating existing cellular machinery. For instance, binding to receptors can trigger the opening of channels, leading to immediate changes in and concentrations that propagate signals across cells. One prominent type of immediate response is the opening of ion channels, exemplified by in neurons upon of glutamate receptors. Glutamate binding to ionotropic receptors, such as and NMDA types, opens cation-permeable channels, allowing influx of Na⁺ and Ca²⁺ ions, which rapidly the postsynaptic membrane and facilitates synaptic transmission. This process occurs on a millisecond timescale, enabling fast excitatory signaling in the . Similarly, cytoskeletal rearrangements represent another key short-term effect, driven by Rho GTPases that regulate dynamics for cell motility. of RhoA, for example, promotes formation and contractility, while Rac1 and Cdc42 induce lamellipodia and extension, respectively, allowing cells to migrate in response to chemotactic signals within minutes. Illustrative examples highlight the physiological relevance of these responses. In insulin signaling, receptor activation leads to the translocation of glucose transporters from intracellular vesicles to the plasma membrane, enhancing in adipocytes and muscle cells within minutes to support metabolic homeostasis. Likewise, Ca²⁺ release from intracellular stores, often triggered by (IP3), induces by binding to , which exposes actin-myosin binding sites, or promotes in secretory cells, such as release from synaptic vesicles. These effects are mediated by second messengers that amplify signals and activate effectors. Cyclic AMP (cAMP), generated by upon G-protein-coupled receptor activation, binds to (PKA), which phosphorylates ion channels and enzymes to alter their activity, such as opening cAMP-gated channels in sensory neurons. IP3, produced by , releases Ca²⁺ from the , which in turn activates calmodulin-dependent kinases to phosphorylate targets involved in contraction or . Such mechanisms ensure responses are confined to seconds to minutes, allowing precise and transient cellular adjustments. Physiologically, these rapid effects underpin critical processes like synaptic transmission for neural communication, hormone-induced in endocrine cells, and acute stress responses that mobilize reserves. For example, epinephrine signaling via cAMP rapidly increases in liver cells to elevate blood glucose during fight-or-flight scenarios. These responses are inherently reversible and energy-efficient, relying on post-translational modifications rather than protein synthesis, which facilitates quick recovery. Disruptions in these pathways, such as mutations in ion channels leading to channelopathies, can result in disorders like , where aberrant channel opening causes hyperexcitability and seizures in neurons.

Long-term gene regulation

Cell signaling pathways often culminate in long-term alterations to gene expression, enabling sustained cellular adaptations such as differentiation and proliferation. These changes are primarily mediated through the activation and nuclear translocation of transcription factors, which bind to specific DNA sequences to regulate target genes over hours to days. For instance, in the mitogen-activated protein kinase (MAPK) pathway, extracellular signal-regulated kinase (ERK) phosphorylates the transcription factor Elk-1, promoting its activation and subsequent induction of immediate early genes like Fos and Egr1. Similarly, in the nuclear factor kappa B (NF-κB) pathway, signaling triggers the phosphorylation and ubiquitin-mediated degradation of the inhibitor IκB, releasing NF-κB dimers for nuclear translocation and binding to κB sites in promoters of genes involved in inflammation and survival. Steroid hormone receptors exemplify direct genomic regulation, where ligand binding induces conformational changes, nuclear localization, and dimerization, allowing the receptor-hormone complex to bind hormone response elements (HREs) on DNA and recruit co-activators to initiate transcription of target genes. In cytokine signaling, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway facilitates rapid nuclear entry of phosphorylated STAT dimers, which bind interferon-stimulated response elements (ISREs) to activate hundreds of interferon-stimulated genes (ISGs) critical for antiviral defense and immune modulation. These transcription factors often interface with chromatin remodeling processes to facilitate enhancer activation and epigenetic modifications, ensuring stable gene expression changes. Chromatin remodelers, such as complexes, reposition nucleosomes at enhancers in response to signaling cues, increasing accessibility for transcription factor binding and promoting enhancer-promoter looping. Epigenetic mechanisms, including histone acetylation by co-activators like (CBP) and p300, further enhance this by neutralizing chromatin charge and recruiting additional factors to poised regulatory elements. The resulting gene expression programs drive profound outcomes, including shifts in cell fate; for example, , a myogenic regulatory factor activated downstream of signaling pathways like Wnt, binds enhancers to orchestrate the transcriptional network for differentiation during . These long-term effects, lasting from hours to days, contrast with transient metabolic responses by embedding persistent epigenetic marks that maintain altered cellular identity. Long-term gene regulation integrates inputs from multiple signaling pathways to fine-tune developmental processes, such as the interplay between Notch and Wnt in embryogenesis, where Notch intracellular domain suppresses Wnt targets while co-regulating for somitogenesis and tissue patterning. Recent advances in single-cell sequencing (scRNA-seq) have illuminated these pathway-gene linkages at cellular resolution, revealing heterogeneous responses and novel regulatory networks in contexts like immune activation and development since 2015.

Regulation and Modulation

Receptor desensitization

Receptor desensitization refers to the adaptive processes that attenuate cellular responsiveness to persistent or repeated stimulation, thereby preventing excessive signaling and maintaining . This phenomenon occurs at multiple levels, including rapid uncoupling of receptors from downstream effectors and longer-term reduction in receptor availability through trafficking. These mechanisms are crucial for modulating signal duration and intensity across various receptor families, such as G protein-coupled receptors (GPCRs) and (RTKs). Short-term desensitization primarily involves post-translational modifications that inactivate receptors within seconds to minutes. For GPCRs, agonist binding induces phosphorylation of serine and threonine residues in the receptor's cytoplasmic domains by G protein-coupled receptor kinases (GRKs), such as GRK2 and GRK3. This phosphorylation recruits β-arrestins (e.g., β-arrestin1 and β-arrestin2), which bind to the phosphorylated receptor and sterically hinder G protein coupling, thereby uncoupling the receptor from its signaling partners and terminating G protein-mediated responses like cAMP production. β-Arrestins not only block signaling but also serve as scaffolds for additional regulatory proteins, further fine-tuning the response. In RTKs, analogous rapid inactivation can occur through autophosphorylation followed by recruitment of inhibitory phosphatases or adaptors, though the emphasis here is on subsequent trafficking events. These acute processes protect cells from overstimulation, as unchecked activation could lead to toxicity or pathological states. A key mechanism for longer-term desensitization is receptor internalization via endocytosis, which removes receptors from the cell surface and either recycles them or directs them to degradation. In GPCRs, β-arrestin-bound receptors are internalized through clathrin-coated pits, involving adaptor proteins like AP-2, leading to sequestration in endosomes. Depending on the receptor and ligand, internalized GPCRs may recycle to the plasma membrane to restore sensitivity or be sorted to lysosomes for degradation, balancing responsiveness. For RTKs, such as the epidermal growth factor receptor (EGFR), ligand-induced dimerization triggers ubiquitination by E3 ligases like c-Cbl, marking the receptor for clathrin-mediated endocytosis. Ubiquitinated RTKs are then trafficked through early endosomes to multivesicular bodies and ultimately to lysosomes, where degradation attenuates signaling and downregulates surface receptor levels. This recycling versus degradation dichotomy allows cells to adapt sensitivity based on stimulus duration. Illustrative examples highlight the physiological and pathological implications of desensitization. In opioid tolerance, chronic exposure to agonists like induces μ-opioid receptor () phosphorylation by GRK2/3, followed by β-arrestin recruitment and internalization, reducing analgesic efficacy and contributing to —a rapid loss of response to repeated stimulation. Similarly, in cancer, impaired EGFR internalization and degradation, or compensatory pathway , can contribute to resistance against targeted therapies like , sustaining oncogenic signaling despite initial promotion of internalization. Recent models incorporating biased agonism, where ligands preferentially activate or β-arrestin pathways, have refined our understanding since the 2010s, revealing how pathway-specific desensitization influences therapeutic outcomes without uniform attenuation. Overall, these processes prevent overstimulation during chronic exposure, with emerging as a hallmark of adaptive desensitization.

Feedback mechanisms

Feedback mechanisms in cell signaling are system-level controls that maintain by fine-tuning the activity of signaling networks through and loops. These loops enable cells to respond adaptively to stimuli, preventing overactivation or insufficient signaling, and contribute to the robustness of biological systems. typically inhibits pathway components to terminate or attenuate signals, while amplifies responses, often creating bistable switches for decisive cellular decisions such as differentiation. Negative feedback loops inhibit signaling pathways to prevent excessive activation and promote signal termination. In insulin signaling, Akt and its downstream effectors, such as S6K1, phosphorylate substrate-1 (IRS-1) on serine residues, which dampens IRS-1's ability to recruit downstream effectors and thus attenuates the pathway. Similarly, protein phosphatase 2A (PP2A) acts as a negative regulator in the ERK/MAPK cascade by dephosphorylating activated ERK1/2 and MEK1/2, thereby reducing signal propagation and restoring basal states. Positive feedback loops amplify signals to generate switch-like behaviors, facilitating rapid transitions in cellular states. In the MAPK pathway, Ras-GTP enhances the (GEF) activity of SOS, which further activates Ras, creating a bistable switch that supports differentiation processes, such as in PC-12 cells responding to EGF. Network integration occurs through crosstalk between pathways and organization by scaffold proteins, allowing coordinated regulation via feedback. For instance, PI3K/AKT signaling inhibits GSK3β through Ser9 , stabilizing β-catenin and enhancing Wnt pathway activity, which promotes transcriptional responses like EMT in cancer contexts. Scaffold proteins, such as A-kinase anchoring proteins (AKAPs), organize kinases and phosphatases into complexes, recruiting termination enzymes like PP2A to enforce and modulate network dynamics. Representative examples illustrate these mechanisms in broader physiological contexts. In circadian rhythms, the PER/CRY complex forms a loop by rhythmically inhibiting CLOCK:BMAL1 transcriptional activity, with PER2 serving as a scaffold to bridge CRY and repressors, ensuring oscillatory essential for daily cycles. In immune tolerance, CTLA-4 on regulatory T cells provides by competing with for / ligands on antigen-presenting cells, dampening T cell activation and preventing . These feedback mechanisms ensure signaling robustness by buffering perturbations and maintaining steady states. Dysregulation of feedback loops contributes to diseases; for example, dysregulated positive feedback loops in Th17 cell signaling, such as IL-17-induced IL-6 production amplifying via /, underlie conditions like and experimental autoimmune encephalomyelitis. approaches, including dynamic differential equation models of gene regulatory networks, quantify loop strengths and interactions in the 2020s, enabling predictions of signaling outcomes in and .

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