Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as aseries of molecular events. Proteins responsible for detecting stimuli are generally termedreceptors, although in some cases the term sensor is used.[1] The changes elicited byligand binding (or signal sensing) in a receptor give rise to abiochemical cascade, which is a chain of biochemical events known as asignaling pathway.
When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events.[2] At the molecular level, such responses include changes in thetranscription ortranslation of genes, andpost-translational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controllingcell growth, proliferation,metabolism and many other processes.[3] In multicellular organisms, signal transduction pathways regulatecell communication in a wide variety of ways.
Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus.Ligands are termedfirst messengers, while receptors are thesignal transducers, which then activateprimary effectors. Such effectors are typically proteins and are often linked tosecond messengers, which can activatesecondary effectors, and so on. Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signaling molecule can generate a response involving hundreds to millions of molecules.[4] As with other signals, the transduction of biological signals is characterised by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological.[5] With the advent ofcomputational biology, theanalysis of signaling pathways and networks has become an essential tool to understand cellular functions anddisease, including signaling rewiring mechanisms underlying responses to acquired drug resistance.[6]
The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence ofEGF, to intracellular events, such as the DNA damage resulting fromreplicativetelomere attrition.[7] Traditionally, signals that reach the central nervous system are classified assenses. These are transmitted fromneuron to neuron in a process calledsynaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.[8]
The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known asreceptor activation. Most ligands are soluble molecules from the extracellular medium which bind tocell surface receptors. These includegrowth factors,cytokines andneurotransmitters. Components of theextracellular matrix such asfibronectin andhyaluronan can also bind to such receptors (integrins andCD44, respectively). In addition, some molecules such assteroid hormones are lipid-soluble and thus cross the plasma membrane to reach cytoplasmic ornuclear receptors.[9] In the case ofsteroid hormone receptors, their stimulation leads to binding to thepromoter region of steroid-responsive genes.[10]
Not all classifications of signaling molecules take into account the molecular nature of each class member. For example,odorants belong to a wide range of molecular classes,[11] as do neurotransmitters, which range in size from small molecules such asdopamine[12] toneuropeptides such asendorphins.[13] Moreover, some molecules may fit into more than one class, e.g.epinephrine is a neurotransmitter when secreted by thecentral nervous system and a hormone when secreted by theadrenal medulla.[14]
Some receptors such asHER2 are capable ofligand-independent activation when overexpressed or mutated. This leads to constitutive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of otherEGFRs, constitutive activation leads to hyperproliferation andcancer.[15]
The prevalence ofbasement membranes in the tissues ofEumetazoans means that most cell types requireattachment to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum. Such signaling is mainly orchestrated infocal adhesions, regions where theintegrin-boundactincytoskeleton detects changes and transmits them downstream throughYAP1.[16] Calcium-dependentcell adhesion molecules such ascadherins andselectins can also mediate mechanotransduction.[17] Specialised forms of mechanotransduction within the nervous system are responsible formechanosensation:hearing,touch,proprioception andbalance.[18]
Cellular and systemic control ofosmotic pressure (the difference inosmolarity between thecytosol and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction).[19] These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors aretransient receptor potential channels present in theprimary cilium of human cells.[19][20] In yeast, the HOG pathway has been extensively characterised.[21]
The sensing of temperature in cells is known as thermoception and is primarily mediated bytransient receptor potential channels.[22] Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, theheat-shock response. Such response is triggered when high temperatures cause the dissociation of inactiveHSF1 from complexes withheat shock proteinsHsp40/Hsp70 andHsp90. With help from thencRNAhsr1, HSF1 then trimerizes, becoming active and upregulating the expression of its target genes.[23] Many other thermosensory mechanisms exist in bothprokaryotes andeukaryotes.[22]
In mammals,light controls the sense ofsight and thecircadian clock by activating light-sensitive proteins inphotoreceptor cells in theeye'sretina. In the case of vision, light is detected byrhodopsin inrod andcone cells.[24] In the case of the circadian clock, a differentphotopigment,melanopsin, is responsible for detecting light inintrinsically photosensitive retinal ganglion cells.[25]
Receptors can be roughly divided into two major classes:intracellular andextracellular receptors.
Extracellular receptors areintegral transmembrane proteins and make up most receptors. They span theplasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in theconformation of the inside part of the receptor, a process sometimes called "receptor activation".[26] This results in either the activation of an enzyme domain of the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.[citation needed]
Ineukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples includetyrosine kinase andphosphatases. Often such enzymes are covalently linked to the receptor. Some of them createsecond messengers such ascyclic AMP andIP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact withadaptor proteins that facilitate signaling protein interactions and coordination of signaling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.[citation needed]
Many adaptor proteins and enzymes activated as part of signal transduction possess specializedprotein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to theEF hand domains ofcalmodulin, allowing it to bind and activatecalmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to thePleckstrin homology domains of proteins such as the kinase proteinAKT.
G protein–coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimericG protein. With nearly 800 members, this is the largest family of membrane proteins and receptors in mammals. Counting all animal species, they add up to over 5000.[27] Mammalian GPCRs are classified into 5 major families:rhodopsin-like,secretin-like,metabotropic glutamate,adhesion andfrizzled/smoothened, with a few GPCR groups being difficult to classify due to low sequence similarity, e.g.vomeronasal receptors.[27] Other classes exist in eukaryotes, such as theDictyosteliumcyclic AMP receptors andfungal mating pheromone receptors.[27]
Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; the G protein exists as a heterotrimer consisting of Gα, Gβ, and Gγ subunits.[28] Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules.[29] The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such asphospholipases andion channels, the latter permitting the release of second messenger molecules.[30] The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity; e.g. via protein kinase phosphorylation or b-arrestin-dependent internalization.[citation needed]
A study was conducted where apoint mutation was inserted into the gene encoding thechemokine receptor CXCR2; mutated cells underwent amalignant transformation due to theexpression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development.[31]
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellularkinase domain and an extracellular domain that bindsligands; examples includegrowth factor receptors such as theinsulin receptor.[32] To perform signal transduction, RTKs need to formdimers in theplasma membrane;[33] the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation oftyrosine residues within the intracellular kinase domains of the RTKs, causing conformational changes. Subsequent to this, the receptors' kinase domains are activated, initiatingphosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such ascell differentiation andmetabolism.[32] Many Ser/Thr and dual-specificityprotein kinases are important for signal transduction, either acting downstream of [receptor tyrosine kinases], or as membrane-embedded or cell-soluble versions in their own right. The process of signal transduction involves around 560 knownprotein kinases andpseudokinases, encoded by the humankinome[34][35]
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of theRas,Rho, and Raf families, referred to collectively assmall G proteins. They act as molecular switches usually tethered to membranes byisoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activateguanine nucleotide exchange factors such asSOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in theexpression of receptors that exist in a constitutively activated state; such mutated genes may act asoncogenes.[36]
Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.[37]
Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and theextracellular matrix and in the transduction of signals from extracellular matrix components such asfibronectin andcollagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator beingintegrin-linked kinase.[38] As shown in the adjacent picture, cooperative integrin-RTK signaling determines the timing of cellular survival,apoptosis,proliferation, anddifferentiation.
Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such asepithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulatingleukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are activated only in response to stimuli such as those received at the site of aninflammatory response. In a similar manner, integrins at the cell membrane of circulatingplatelets are normally kept inactive to avoidthrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.[39]
In plants, there are no bona fide integrin receptors identified to date; nevertheless, several integrin-like proteins were proposed based on structural homology with the metazoan receptors.[40] Plants contain integrin-linked kinases that are very similar in their primary structure with the animal ILKs. In the experimental model plantArabidopsis thaliana, one of the integrin-linked kinase genes,ILK1, has been shown to be a critical element in the plant immune response to signal molecules from bacterial pathogens and plant sensitivity to salt and osmotic stress.[41] ILK1 protein interacts with the high-affinity potassium transporterHAK5 and with the calcium sensor CML9.[41][42]
When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which areMyd88,TIRAP,TRIF, andTRAM.[43][44][45] These adapters activate other intracellular molecules such asIRAK1,IRAK4,TBK1, andIKKi that amplify the signal, eventually leading to theinduction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.
A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neuralsynapse. The influx of ions that occurs in response to the opening of these channels inducesaction potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling thedendritic spines involved in the synapse.
Intracellular receptors, such asnuclear receptors andcytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like thesteroid hormonestestosterone andprogesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through thenuclear membrane into thenucleus, altering gene expression.
Activated nuclear receptors attach to the DNA at receptor-specifichormone-responsive element (HRE) sequences, located in thepromoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors ofgene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.
Nucleic receptors have DNA-binding domains containingzinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible fordimerization of nucleic receptors prior to binding and providing structures fortransactivation used for communication with the translational apparatus.
Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol. In the absence of steroids, they associate in an aporeceptor complex containingchaperone orheatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein tofold in a way such that thesignal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden. Receptor activity can be enhanced by phosphorylation ofserine residues at their N-terminal as a result of another signal transduction pathway, a process calledcrosstalk.
Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from aprecursor likeretinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand likeprostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs. They repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.
Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identifiedNOD-like receptors (NLRs) reside in the cytoplasm of someeukaryotic cells and interact with ligands using aleucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules likeNOD2 interact withRIP2 kinase that activatesNF-κB signaling, whereas others likeNALP3 interact with inflammatorycaspases and initiate processing of particularcytokines likeinterleukin-1β.[46][47]
First messengers are the signaling molecules (hormones, neurotransmitters, and paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response. In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.
The release of calcium ions from theendoplasmic reticulum into thecytosol results in its binding to signaling proteins that are then activated; it is then sequestered in thesmooth endoplasmic reticulum[48] and themitochondria. Two combined receptor/ion channel proteins control the transport of calcium: theInsP3-receptor that transports calcium upon interaction withinositol triphosphate on its cytosolic side; and theryanodine receptor named after thealkaloidryanodine, similar to the InsP3 receptor but having afeedback mechanism that releases more calcium upon binding with it. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its free state concentration is very low and is mostly bound to organelle molecules likecalreticulin when inactive.
Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings, andcell migration. The three main pathways that lead to its activation are GPCR pathways, RTK pathways, and gated ion channels; it regulates proteins either directly or by binding to an enzyme.
Lipophilic second messenger molecules are derived from lipids residing in cellular membranes; enzymes stimulated by activated receptors activate the lipids by modifying them. Examples includediacylglycerol andceramide, the former required for the activation ofprotein kinase C.
Nitric oxide (NO) acts as a second messenger because it is afree radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised fromarginine and oxygen by theNO synthase and works through activation ofsoluble guanylyl cyclase, which when activated produces another second messenger, cGMP. NO can also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage duringstroke, but is the cause of many other functions like the relaxation of blood vessels,apoptosis, and penileerections.
In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process calledredox signaling. Examples includesuperoxide,hydrogen peroxide,carbon monoxide, andhydrogen sulfide. Redox signaling also includes active modulation of electronic flows insemiconductive biological macromolecules.[49]
Gene activations[50] and metabolism alterations[51] are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream[51] and the migration ofneutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as agenetic program.[52]
Mammalian cells require stimulation for cell division and survival; in the absence ofgrowth factor,apoptosis ensues. Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and multicellular organisms; signal transduction pathways are perceived to be so central to biological processes that a large number of diseases are attributed to their dysregulation.Three basic signals determine cellular growth:
The combination of these signals is integrated into altered cytoplasmic machinery which leads to altered cell behaviour.
Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses.
The earliest notion of signal transduction can be traced back to 1855, whenClaude Bernard proposed that ductless glands such as thespleen, thethyroid andadrenal glands, were responsible for the release of "internal secretions" with physiological effects.[57] Bernard's "secretions" were later named "hormones" byErnest Starling in 1905.[58] Together withWilliam Bayliss, Starling had discoveredsecretin in 1902.[57] Although many other hormones, most notablyinsulin, were discovered in the following years, the mechanisms remained largely unknown.
The discovery ofnerve growth factor byRita Levi-Montalcini in 1954, andepidermal growth factor byStanley Cohen in 1962, led to more detailed insights into the molecular basis of cell signaling, in particulargrowth factors.[59] Their work, together withEarl Wilbur Sutherland's discovery ofcyclic AMP in 1956, prompted the redefinition ofendocrine signaling to include only signaling from glands, while the termsautocrine andparacrine began to be used.[60] Sutherland was awarded the 1971Nobel Prize in Physiology or Medicine, while Levi-Montalcini and Cohen shared it in 1986.
In 1970,Martin Rodbell examined the effects ofglucagon on a rat's liver cell membrane receptor. He noted thatguanosine triphosphate disassociated glucagon from this receptor and stimulated theG-protein, which strongly influenced the cell's metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell.[61] For this, he shared the 1994Nobel Prize in Physiology or Medicine withAlfred G. Gilman. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in 1972.[62] Some early articles used the termssignal transmission andsensory transduction.[63][64] In 2007, a total of 48,377 scientific papers—including 11,211review papers—were published on the subject. The term first appeared in a paper's title in 1979.[65][66] Widespread use of the term has been traced to a 1980 review article by Rodbell:[61][67] Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.[47]
The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology.
The relevant events begin with the sequencing ofmyeloma protein light chains, which are found in abundance in the urine of individuals withmultiple myeloma. Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or theFragment crystallizable region).[68] An analysis of multiple V region sequences by Wu and Kabat[69] identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of biological function through the Fc domain. Crystallization of an IgG molecule soon followed[70] ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution.
The biological significance of these developments was encapsulated in the theory ofclonal selection[71] which holds that aB cell has on its surface immunoglobulin receptors whose antigen-binding site is identical to that of antibodies that are secreted by the cell when it encounters an antigen, and more specifically a particular B cell clone secretes antibodies with identical sequences. The final piece of the story, theFluid mosaic model of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction; viz, receptor dimerization.
The first hints of this were obtained by Becker et al[72] who demonstrated that the extent to which humanbasophils—for which bivalentImmunoglobulin E (IgE) functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalentligand is used. The latter observation was consistent with earlier findings by Fanger et al.[73] These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in[74]) in a variety of cell types, including B cells.
Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell[75] which resolved an apparent paradox: clustering forms stable networks; i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increase as the immune response progresses. A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed byDeLisi and Perelson[76] who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand. Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators,[77][78] all aimed at the analysis of dose-response patterns of immune cells and their biological correlates.[79] For a recent review of clustering in immunological systems see.[80]
Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is a detection and response to concentration gradients by bacteria[81]-–the classic mathematical theory appearing in.[82] A recent account can be found in[83]
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