This initial neural fold is of anterior character and exposure to additional posteriorizing signals, such as Wnt ligands, retinoic acid and fibroblast growth factor, is utilized to define the prospective neural crest. As outlined above, Wnts play a critical role in determining cell fate during embryogenesis Aybar et al. In adult individuals, however, excessive signaling through this same pathway is strongly implicated in tumorigenesis, since mutations in downstream elements are associated in a causative manner with the development of different types of cancers.
In the canonical Wnt signaling pathway b -catenin pathway , multiprotein complexes play a crucial role by regulating b -catenin degradation via the proteasome pathway.
Wnt signaling via its receptor Frizzled blocks this sequence. Several oncogenes and tumor suppressors are implicated with varying frequencies. Ras-dependent signaling involves amongst many other possibilities, activation of the mitogen-activated-protein kinase MAPK cascade. This evolutionarily highly conserved signaling cascade is another excellent example in which complex formation between individual pathway elements and scaffolding proteins are essential for efficient signal transduction.
Interestingly, oncogenic ras induces a senescence-like permanent growth arrest phenotype in primary cells, suggesting that cells may avoid oncogene-mediated transformation by inducing senescence Lin and Lowe, Sierra and coworkers have identified genes that are specifically over-expressed in rats as they approach the end of their lifespan. Serum levels of T-kininogen T-KG were found to increase dramatically in these animals. Upon overexpression of T-KG in both fibroblasts and endothelial cells, proliferation was dramatically reduced.
Thus, senescence may be viewed as a potential safeguard against neoplasia in aging individuals. As apparent so far, generation of intracellular signals often occurs at or near the plasma membrane. Multi-protein complex formation in receptor proximity represents an initial crucial step that is reasonably well understood for many signaling pathways. A big part of the challenge ahead resides in understanding how these signals traverse the cytosol and ultimately lead to alterations in gene expression.
Nuclear receptors are a family of transcription factors that essentially bypass this sequence by directly regulating transcription in a ligand-dependent manner. Despite the apparent differences, activation or repression of gene expression by such receptors is intimately linked to the formation of complexes with molecules that serve as co-activators or co-repressors by modifying local DNA structure. Alterations in signaling events linked to this receptor family are associated with various human cancers Hart, Long-term cellular responses involve not only changes in gene transcription but also protein synthesis.
What remains largely unrecognized is that most of what is generated by the translational machinery is more of precisely the same components. For instance, in an exponentially growing carcinoma cell ribosomes or ribosomal proteins are synthesized per minute. Thus, synthesis of ribosomal components is easily the most energy-consuming anabolic process in a growing cell and precise control is mandatory to avoid unnecessary depletion of energy reserves. S6Kinase S6K phosphorylates the 40S ribosomal protein S6 and thereby increases translation of mRNAs coding for components of the protein synthesis machinery.
Here, G. Thomas describes how lack of S6K in flies and mice leads to the generation of smaller individuals. This probably is due to decreased protein synthesis that results in smaller cells. Surprisingly, in the mouse, such S6K deficiency led to glucose intolerance associated with hypoinsulinemia that could be accounted for by a reduction in size of the b cells in Langerhans islets Thomas, In summary, formation of multi-protein complexes is an essential if not defining feature of eukaryotic signaling.
Clearly, we now appreciate this fact and are beginning to grasp some of the underlying guiding principles. However, much remains yet to be accomplished. The hope is that insights to these mechanisms will not only further our understanding of fundamental processes in biology like signal transduction, but will also help in the development of new strategies to treat human disease.
Cancer Res J Cell Sci Biosynthetic intermediates and lipid second messengers. Biol Res [ Links ] Received: July 10, In revised form: July 30, Servicios Personalizados Revista. It is common for a single receptor to bind and be activated by more than one extracellular ligand. For example, the prolactin cytokine receptor can engage both growth hormone and prolactin. Structural and mutagenesis analysis has indicated that the ligand-binding sites of cell surface receptors may be rather adaptable, composed of relatively hydrophobic yet solvent accessible surfaces Cunningham and Wells ; Lowman et al.
Although the ligand-binding surfaces are quite large, only a few residues are critical for ligand recognition. In the example cited above, the two hormones recognize overlapping sites on the same receptor, but are dependent on distinct residues for high affinity binding.
Such data suggest that receptors combine selectivity for specific ligands with the potential for flexibility and possibility for rapid evolution of hormone recognition. As discussed below, protein—protein interactions within the cell that control cytoplasmic signaling pathways display many of the same characteristics.
In addition to the formation of multichain receptors through the interactions of distinct subunits, recent data suggest that entirely different receptors may directly interact with one another at the surface of the same cell. This leads to the possibility of cross-talk between separate receptors and pathways at the very earliest steps in signaling.
This association leads to a mutual inhibition of the two receptors and provides a mechanism through which a GPCR may influence synaptic strength independently of G protein signaling. These types of interaction are not confined to the nervous system. For example, the Kit RTK, which is activated by the hematopoietic stem cell factor, can bind and phosphorylate the cytoplasmic region of the erythropoietin cytokine receptor Wu et al.
The involvement of modular protein—protein interactions in signaling from cell surface receptors was originally recognized in the context of RTKs. As noted above, receptor activation leads to the intermolecular phosphorylation of receptor chains at sites that consequently bind proteins with SH2 domains Pawson ; Kuriyan and Cowburn As with many interaction modules, the amino and carboxyl termini of SH2 domains are close together in space, and on the opposite face from the ligand-binding surface.
This potentially allows an SH2 domain to be inserted into a host protein at an internal location, while leaving the phosphopeptide-binding surface free to engage ligands. Most SH2 domains require phosphorylation of the peptide ligand for high affinity binding, but differ in their ability to recognize residues carboxy-terminal to the pTyr, thereby imbuing each SH2 domain with an ability to bind preferentially to a specific phosphorylated motif Songyang et al.
Thus, in the case of activated RTKs, their ability to stimulate cytoplasmic signaling pathways is to some extent determined by the sequence contexts of their autophosphorylation sites, which in turn dictates which SH2-containing proteins will engage the autophosphorylated receptor. SH2 domains must therefore achieve something of a balancing act. Their affinity for an unphosphorylated site must not be too high, or binding could not be regulated by phosphorylation, yet they must gain sufficient binding energy from the recognition of more carboxy-terminal residues to allow discrimination between different sites.
Furthermore, their off-rates must be sufficiently high to allow for rapid signal transduction. Perhaps for this reason the interactions of SH2 domains with phosphopeptide motifs can be highly dynamic Kay et al. This leads to the possibility that SH2 domain binding specificity results from a combination of permissive and inhibitory forces.
Thus compatible residues in the SH2 domain and ligand will promote binding, whereas residues that sterically interfere with phosphopeptide recognition will inhibit recognition. The potential flexibility of SH2 domains is emphasized by the ability of single amino acid substitutions to alter binding specificity Fig.
This apparent flexibility may have an evolutionary advantage, in the sense that SH2 domain binding specificity might change rather rapidly, allowing the formation of new signaling connections as metazoan organisms became more complex. Evolution of SH2 domain-binding specificity. In each case the pTyr is to the right. The relevance of specific SH2 domain-mediated interactions to biological signaling pathways has also been tested by introducing mutations into SH2 docking sites on receptors.
A nice example is provided by the EGF receptor homolog in C. The three carboxy-terminal autophosphorylation sites Y6—8 lie in YXN motifs that can bind the worm Grb2 adaptor and thereby activate the Ras pathway. These sites have a redundant role in vulval formation and viability but are not required for ovulation.
In the mammalian system, the Met receptor tyrosine kinase has two closely spaced Tyr phosphorylation sites within its carboxy-terminal tail, that bind a number of SH2-containing proteins. Substitution of both Tyr residues with Phe in the mouse causes embryonic lethality similar to that seen with a null allele, suggesting that although the receptor retains kinase activity, it is functionally impotent when stripped of its SH2-docking sites Maina et al.
However, PI3K-binding is not significantly required for Kit's role in melanogenesis and hematopoiesis. These data are consistent with the view that individual receptor phosphorylation sites bind SH2 signaling proteins in a sequence-dependent manner, resulting in the activation of defined biochemical pathways and specific biological responses. There are a number of complications to this simple view.
First, different signaling pathways may ultimately converge on overlapping targets, and thus have partially redundant functions Fambrough et al. Second, some signaling pathways may have subtle biological activities.
Furthermore, some RTKs can phosphorylate specific docking proteins at residues that subsequently bind SH2 proteins, and provide signaling activity even in the absence of SH2-binding sites on the receptor itself. These characteristically possess a means of membrane attachment, a receptor-binding PTB domain, and multiple sites for tyrosine phosphorylation and SH2-binding Sun et al. It is instructive to consider how these docking proteins are recruited to activated receptors.
Interestingly, a growing number of proteins have been found to possess PTB domains that bind NPXY, or related, motifs but do not require phosphorylation for high affinity binding Borg et al. This has led to the notion that PTB domains originally evolved to recognize non-phosphorylated peptide motifs, and subsequently developed a capacity for pTyr-binding in specific cases.
Rather strikingly, PTB domains have a similar structural fold to PH domains which bind phospholipids and EVH1 domains which bind proline-rich motifs , as well as to a protein that binds the Ran GTPase, suggesting that this is a rather versatile scaffold that has been exploited for several different protein and phospholipid recognition events Yoon et al. Modular protein—protein interaction domains convey signals from activated receptors using a variety of recognition motifs.
FADD recruits procaspase 8, which initiates a proteolytic cascade resulting in apoptosis. Activated Ras can potentially stimulate multiple pathways to promote cell survival, activate transcription, or cause cytoskeletal rearrangement. What purpose is served by docking proteins that associate with RTKs? One possibility is that they amplify signaling from a given receptor to a particular biochemical pathway. Another role for a docking protein may be to juxtapose cytoplasmic proteins that act at successive stages of a pathway.
An example is provided by the SLP protein that functions downstream of the T-cell antigen receptor. SLP therefore functions as a scaffold that juxtaposes members of a pathway targeting the cytoskeleton Bubeck Wardenburg et al.
EH domains recognize Asn—Pro—Phe sequences, commonly found in polypeptides involved in protein trafficking Salcini et al. Two folded PDZ domains can also bind directly to one another Hillier et al. As well as modules involved in domain—peptide or domain—domain interactions, there are several examples of domains that bind selectively to phospholipids and thereby target proteins to specific sites in the membrane to directly regulate their activity or access to substrates. In particular, FYVE domains frequently bind specific phosphoinositides, and therefore thereby mediate the effects of PI kinases on cellular behaviour Fruman et al.
Recent evidence suggests that the homodimerization of PH and FYVE domains may increase the avidity with which they bind membrane sites Mao et al. In many cases, cytoplasmic signaling proteins possess multiple protein—protein and protein—phospholipid interaction domains, covalently linked in various combinations.
The joining of different domains can serve a variety of functions. Two domains may interact with different sites on the same target, as commonly occurs with polypeptides that possess tandem SH2 domains, thereby increasing both the affinity and specificity of the interaction Ottinger et al. Conversely, separate domains may interact with distinct partners, as observed for adaptors with SH2 and SH3 domains, such as Grb2 that links activated receptors to downstream targets with proline-rich motifs, notably the Ras GEF Sos1 Li et al.
Furthermore, modular domains can engage in complex intramolecular interactions that regulate the enzymatic activities of their host protein, as occurs in the Src family kinases or the Shp2 tyrosine phosphatase Sicheri et al. These roles are not necessarily mutually exclusive. In the Src tyrosine kinase, phosphorylation of a carboxy-terminal tyrosine leads to intramolecular interactions in which the SH2 and SH3 domains engage internal ligands and block kinase activity. However, once these intramolecular interactions are broken, the SH3 and SH2 domains play an important role in tethering Src to its substrates and in promoting processive phosphorylation Sakai et al.
The process through which protein—protein interactions mediate phosphotyrosine signaling represents a specific aspect of a more general process in signal transduction. The Smad proteins have an amino-terminal MH1 domain, a central linker, and a carboxy-terminal MH2 domain, which recognizes the type I receptor. R-Smad phosphorylation appears to block an internal interaction between the MH1 and MH2 domains, and free the MH2 domain to associate with the so-called common Smad Smad4 , which is not itself phosphorylated.
A binding site has been identified on Smad4 that may serve as a receptor for phosphorylated residues of R-Smads Qin et al. Stats and Smads: Linking receptors to transcription. These act on the cytoplasmic tail of the receptor, creating SH2 docking sites.
STAT proteins are recruited to the membrane via their SH2 domain, and are themselves phosphorylated by the Jak kinases. Phosphorylated STATs dimerize and translocate to the nucleus where they activate transcription by binding directly to specific DNA sequences.
The receptor targets are modular and they form complexes with their receptors. In both cases, phosphorylation regulates protein—protein interactions, although in distinct ways.
Indeed, the regulation of Smad signaling is somewhat reminiscent of Stats, SH2-containing proteins that function downstream of cytokine receptors to control gene expression Darnell Fig.
Stats bind to specific sites on activated cytokine receptors through their SH2 domain, and themselves become phosphorylated, resulting in a mutual SH2-pTyr interaction between two Stat molecules Chen et al. The phosphorylated Stats consequently dimerize, are displaced from the receptor, relocate to the nucleus and bind to specific promoters. Within their linker region, Smads have proline-rich PY motifs that bind the WW domains of another E3 protein—ubiquitin ligase Smurf with a Hect catalytic domain, leading to Smad ubiquitination and destruction Zhu et al.
Thus in both cases modular protein interactions target specific components of the signaling pathway for degradation, in a fashion that appears critical for appropriate biological responses. Members of the tumor necrosis factor TNF receptor family lack catalytic domains, but use specific protein—protein interactions to convey signals from the receptor to their downstream targets. A relatively simple example involves the Fas receptor, which induces cell death upon stimulation with the Fas-ligand Ashkenazi and Dixit Oligomerization of Fas by Fas-L appears to juxtapose chains of procaspase 8 which consequently undergo auto-cleavage, leading to the release of active caspase 8, initiating a cascade of proteolytic events that result in apoptosis Salvesen et al.
Thus, rather like a RTK that engages a modular protein Grb2 , which in turn recruits a signaling enzyme Sos1 to activate the Ras pathway, so Fas binds a modular adaptor, FADD, that couples to the enzyme caspase 8 and lights the apoptotic fuse. These data indicate that receptors involved in signaling pathways that do not use phosphorylation as a primary mechanism for information transfer, nonetheless make use of modular protein—protein interactions to specifically activate their targets.
Thus TNF-R1, like some RTKs, employs a docking protein that associates with multiple downstream targets and can thereby extend the range and potency of receptor signaling. The amino termini of the TRAFs have ring and zinc finger sequences that are responsible for interactions with downstream targets Rothe et al.
Crystal structures of the coiled-coil and TRAF-C regions of TRAF2 indicate that these domains self-associate to form a trimer that is ideally fashioned to bind the activated receptor, which is itself coralled into a trimeric state by its ligand McWhirter et al.
Thus, although TRAFs have only a low affinity for the monomeric receptor, they bind in a co-operative fashion to the oligomerized receptor. Surprisingly, an individual TRAF-C domain can bind through the same groove to peptide motifs that are unrelated in their primary sequences. TRAFs then act as adaptors to link the activated receptors to cytoplasmic targets. Mek is a dual-specificity kinase that phosphorylates and activates Erk a MAPK , which has multiple substrates involved in the regulation of cell growth and proliferation Marshall ; Whitmarsh and Davis Interestingly, PDK1 phosphorylates PKB within the activation loop of the catalytic domain, in a fashion that is indispensable for PKB activation and its subsequent effects on events such as cell survival.
Mammalian cells contain seven isoforms, which form homo- or heterodimers that recognize specific pSer-containing motifs, originally identified as having the consensus Arg-Ser-X-pSer-X-Pro Muslin et al. More recent data have revealed the structural basis for this interaction Yaffe et al. Of particular interest, some of the proteins involved in the signaling pathways mentioned above are bound by proteins following their phosphorylation.
The binding of proteins to phosphorylated targets apparently results in their relocalization and inhibition. In the case of BAD this is achieved by sequestering it away from Bcl-X L , while FKHRL1 is apparently retained in the cytoplasm once complexed to , and is therefore prevented from gaining access to its targets in the nucleus. The ability of proteins to control cellular events through the recognition of specific phosphoproteins is not restricted to conventional signaling pathways responsive to extrinsic cues, but is also important in regulating checkpoints in the cell cycle that monitor intrinsic events such as DNA damage.
In this context, a key step in controlling the passage of mammalian cells through the cell cycle is the serine phosphorylation of Cdc25C, a tyrosine phosphatase that dephosphorylates and activates the critical cyclin-regulated protein kinase Cdc2, and thereby promotes passage of the cell into mitosis.
During interphase Cdc25C is phosphorylated at Ser, resulting in binding to proteins Peng et al. Cdc25C shuttles between the cytoplasm and nucleus, and binding favors the retention of Cdc25C in the cytoplasm, possibly by masking a nuclear localization signal Fig.
As a result Cdc25C is physically separated from its nuclear substrate, which is therefore held in an inactive state. Dephosphorylation of Ser frees Cdc25C to enter the nucleus and initiate mitosis. This blocks the interaction of p53 with Mdm2 that normally results in efficient ubiquitin-targeted degradation of p53 by the proteasome. DNA damage stabilization of p53 thereby blocks cell cycle progression at the G 1 -to-S checkpoint. Cyclin E1 is itself degraded at the G 1 -to-S boundary following phosphorylation on Thr Notably, the Forkhead-associated FHA domain is present in a wide range of nuclear polypeptides involved in transcription, DNA repair or cell cycle progression in both eukaryotes and prokaryotes Hofmann and Butcher Recent work on the yeast protein kinase Rad53 has shown that its amino-terminal FHA domain binds selectively to pThr-X-X-Asp motifs and has suggested that the recognition of phosphorylated peptide motifs may be a common property of FHA domains Durocher et al.
Interestingly, Rad53 lies downstream of its phosphorylated binding partner, Rad9, a protein that senses DNA damage, suggesting that a phosphodependent FHA-mediated interaction is important in checkpoint signaling Sun et al. Consistent with this idea, recent data indicate that the amino-terminal FHA domain of human Chk2, a homolog of yeast Rad53, is affected by mutations in the familial cancer Li—Fraumeni syndrome Bell et al.
Similarly, the WW domain of the peptidyl—prolyl isomerase Pin1 binds pSer—Pro motifs, which may position the enzyme close to its substrates Lu et al. This scheme was first established for a complex of proteins termed SCF that control S phase progression in Saccharomyces cerevisiae , through their ability to degrade their targets in a fashion that imposes order on the cell cycle Willems et al.
In yeast, a protein termed Cdc53 corresponding to the cullins of multicellular organisms serves as a scaffold to recruit an adaptor Skp1 , an E2 protein—ubiquitin ligase Cdc34 , and a ring finger protein Rbx1 , which potentiates substrate ubiquitination. Skp1 links the Cdc53 complex to one of many proteins with a conserved Skp1-binding domain, termed an F box. F-box proteins contain the eponymous F box at the amino terminus and a variable carboxyl terminus, typically comprised of WD40 repeats or leucine-rich repeats, which directly contacts the target for ubiquitination.
In several cases, phosphorylation of the target is required for its association with the F-box protein. This has been nicely demonstrated for the yeast protein Sic1, which is the only essential target for Cdk activity during the G 1 phase of the cell cycle.
Sic1 becomes phosphorylated at multiple serine residues and subsequently associates with the carboxy-terminal WD40 repeats of an F-box protein termed Cdc4, resulting in its degradation.
The targeting of specific proteins for degradation through their association with F-box proteins likely regulates many events in signal transduction Fig. Protein kinases are often anchored to a scaffolding protein that may either facilitate the flow of information from one kinase to another, or hold the kinase in a latent state close to the receptor that will induce its activation Pawson and Scott ; Whitmarsh and Davis Scaffold mediated assembly of signaling pathways.
Jip1 also has SH3 and PTB domains that may tether the complex to additional proteins involved in upstream activation or localization.
Once tethered in this manner, Erk phosphorylates the substrate, Rsk1. In doing so, Yotiao creates close physical association of the components that repress resting NMDA receptor and enhance channel activation. The classical example of this latter type of scaffolding protein is the Ste5 polypeptide in yeast, which is required for growth arrest and mating, and acts downstream of the G-protein coupled pheromone receptor to regulate a MAPK cascade Elion Various functions have been proposed for Ste5, notably to increase the fidelity of the pathway by physically juxtaposing successive kinases, to localize these kinases to specific subcellular compartments, and to insulate interacting kinases from separate pathways.
It is also possible that Ste5 oligomerization could enhance kinase activation by promoting intermolecular autophosphorylation. The potential importance of scaffolding proteins is underscored by the observation that the MAPKKK Ste11 also acts in the yeast osmosensing pathway, although the other components of the pathway, including the Hog1 MAPK are different.
Pbs2 engages both Ste11 and Hog1, as well as the osmosensing receptor Sho1 , which has an SH3 domain that binds a proline-rich motif in Pbs2 Posas and Saito Thus, Pbs2 serves a somewhat analagous function to Ste5 in assembling the elements of a signaling pathway into an individual complex. To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation. Chem Res Toxicol , 19 2 , 01 Feb Cited by: articles PMID: Arch Biochem Biophys , 2 , 24 Jun Plant Physiol , 2 , 01 Jun Physiol Rev , 89 1 , 01 Jan Contact us.
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Nathan C 1. Affiliations 1 author 1. Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract No abstract provided. Free full text. J Clin Invest.
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Go to:. Open in a separate window. Figure 1. Table 1 Types of specificity in intracellular signaling. Table 2 Examples of forced overexpression of intracellular signals during microbial pathogenesis and host defense.
Nathan C. Nitric oxide as a secretory product of mammalian cells. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV EMBO J.
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Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. The prototypic redox-based signaling mechanism. Bogdan C. Nitric oxide and the regulation of gene expression. Trends Cell Biol.
Droge W. Free radicals in the physiological control of cell function. Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nitric oxide synthase is induced in sporulation of Physarum polycephalum. Genes Dev. Nitric oxide regulates cell proliferation during Drosophila development. Nitric oxide is an essential negative regulator of cell proliferation in Xenopus brain.
Klein JA, et al. The harlequin mouse mutation downregulates apoptosis-inducing factor. Gu Z, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Lambeth JD. Ehrt S, et al. Reprogramming of the macrophage transcriptome in response to interferon-gamma and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase.
Requirement for type 2 NO synthase for IL signaling in innate immunity. Signaling networks: the origins of cellular multitasking. Signal transduction. History matters. Strohman R. Maneuvering in the complex path from genotype to phenotype.
Wentworth P, Jr, et al. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Sutherland EW. Studies on the mechanism of hormone action. Smith O. Nobel Prize for NO research. Rich TC, et al. A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell.
Davare MA, et al. Bootman MD, et al. Calcium signalling—an overview. Cell Dev. Vieira OV, et al. Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. Perry SJ, et al. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Dolmetsch R. Excitation-transcription coupling: signaling by ion channels to the nucleus. Calcium oscillations increase the efficiency and specificity of gene expression.
Gene regulation mediated by calcium signals in T lymphocytes. Chen Y, et al. Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Trends Endocrinol. Zippin JH, et al. Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. Regulation of corepressor function by nuclear NADH. Chatterji D, Ojha AK. Revisiting the stringent response, ppGpp and starvation signaling. Dennis PB, et al. Vaziri H, et al. Arner ES, Holmgren A.
In order to explore the underlying mechanism of intercellular signaling pathways, a full range of artificial systems have been explored. However, many of them are complicated and uncontrollable. Herein we designed an artificial signal transduction system able to control the influx of environmental ions by triggering the activation of synthetic transmembrane channels immobilized on giant membrane vesicles GMVs.
This event, in turn, triggers signal responses encapsulated in the GMV A protocell model. By mimicking natural signal transduction pathways, this novel prototype provides a workable tool for investigating cell—cell communication and expands biological signaling systems in general as well as explores useful platforms for addressing scientific problems which involve materials science, chemistry, and medicine.
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