Academic literature on the topic 'Extracellular signalling molecules'
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Journal articles on the topic "Extracellular signalling molecules"
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Chen, Zhen-Ping, Andrew Levy, and Stafford L. Lightman. "Nucleotides as Extracellular Signalling Molecules." Journal of Neuroendocrinology 7, no. 2 (1995): 83–96. http://dx.doi.org/10.1111/j.1365-2826.1995.tb00671.x.
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Gradilla, Ana-Citlali, Eléanor Simon, Gustavo Aguilar, and Isabel Guerrero. "From intra- to extracellular vesicles: extracellular vesicles in developmental signalling." Essays in Biochemistry 62, no. 2 (2018): 215–23. http://dx.doi.org/10.1042/ebc20180001.
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Signalling from cell-to-cell is fundamental for determining differentiation and patterning. This communication can occur between adjacent and distant cells. Extracellular vesicles (EVs) are membrane-based structures thought to facilitate the long-distance movement of signalling molecules. EVs have recently been found to allow the transport of two major developmental signalling pathways: Hedgehog and Wnt. These signalling molecules undergo crucial post-translational lipid modifications, which anchor them to membranes and impede their free release into the extracellular space. Preparation of these ligands in EVs involves intracellular vesicle sorting in an endocytosis-dependent recycling process before secretion. In the present review, we discuss the most recent advances with regard to EV involvement in developmental signalling at a distance. We focus on the role of the protein complexes involved in EV genesis, and provide a comprehensive perspective of the contribution of these complexes to intracellular vesicle sorting of developmental signals for their extracellular secretion, reception and transduction.
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Giuliani, Anna Lisa, Alba Clara Sarti, and Francesco Di Virgilio. "Extracellular nucleotides and nucleosides as signalling molecules." Immunology Letters 205 (January 2019): 16–24. http://dx.doi.org/10.1016/j.imlet.2018.11.006.
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Cantrell, D. A. "Phosphoinositide 3-kinase signalling pathways." Journal of Cell Science 114, no. 8 (2001): 1439–45. http://dx.doi.org/10.1242/jcs.114.8.1439.
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Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3′-OH position of the inositol ring of inositol phospholipids, producing three lipid products: PtdIns(3)P, PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3). These lipids bind to the pleckstrin homology (PH) domains of proteins and control the activity and subcellular localisation of a diverse array of signal transduction molecules. Three major classes of signalling molecule are regulated by binding of D-3 phosphoinositides to PH domains: guanine-nucleotide-exchange proteins for Ρ family GTPases, the TEC family tyrosine kinases such as BTK and ITK in B and T lymphocytes, respectively, and the AGC superfamily of serine/threonine protein kinases. These molecules are activated by a variety of extracellular stimuli and have been implicated in a wide range of cellular processes, including cell cycle progression, cell growth, cell motility, cell adhesion and cell survival.
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Schulze-Lohoff, E., A. Ogilvie, and R. B. Stenzel. "Extracellular nucleotides as signalling molecules for renal mesangial cells." Journal of Autonomic Pharmacology 16, no. 6 (1996): 381–84. http://dx.doi.org/10.1111/j.1474-8673.1996.tb00058.x.
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Humphries, M. J., M. A. Travis, K. Clark, and A. P. Mould. "Mechanisms of integration of cells and extracellular matrices by integrins." Biochemical Society Transactions 32, no. 5 (2004): 822–25. http://dx.doi.org/10.1042/bst0320822.
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While it is self-evident that all extracellular molecules are an integral part of a multicellular organism, it is paradoxical that they are often considered to be dissociated from cells. The reality is that a continuum of dynamic, bi-directional interactions links the intracellular environment through cell-surface receptors to multimolecular extracellular assemblies. These interactions not only control the behaviour of individual cells, but also determine tissue architecture. Adhesion receptor function is partly determined by an ability to tether the contractile cytoskeleton to the plasma membrane, but there is also evidence that integrin receptors modulate signalling events that are essential for cellular differentiation. A major challenge is now to integrate work at the atomic, molecular and cellular levels, and obtain holistic insights into the mechanisms controlling cell adhesion. In the present study, we review current knowledge of the molecular mechanisms employed by cells to integrate with the extracellular matrix. Two main topics are covered: the adaptation of integrin structure for bi-directional signalling and the integration of integrin signalling with other receptors.
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Santos, Jerran, Penelope V. Dalla, and Bruce K. Milthorpe. "A Molecular Analysis of Cytokine Content across Extracellular Vesicles, Secretions, and Intracellular Space from Different Site-Specific Adipose-Derived Stem Cells." International Journal of Molecular Sciences 23, no. 1 (2021): 397. http://dx.doi.org/10.3390/ijms23010397.
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Cytokines are multifunctional small proteins that have a vital influence on inflammatory states of tissues and play a role in signalling and cellular control mechanisms. Cytokine expression has primarily been viewed as a form of direct secretion of molecules through an active transportation; however, other forms of active transport such as extracellular vesicles are at play. This is particularly important in stem cells where signalling molecules are key to communication managing the levels of proliferation, migration, and differentiation into mature cells. This study investigated cytokines from intracellular content, direct cellular secretions, and extracellular vesicles from adult adipose-derived stem cells isolated from three distinct anatomical locations: abdomen, thigh, and chin. The cells were cultured investigated using live cell microscopy, cytokine assays, and bioinformatics analysis. The cytokines quantified and examined from each sample type showed a distinct difference between niche areas and sample types. The varying levels of TNF-alpha, IL-6 and IL-8 cytokines were shown to play a crucial role in signalling pathways such as MAPK, ERK1/2 and JAK-STAT in cells. On the other hand, the chemotactic cytokines IL-1rn, Eotaxin, IP-10 and MCP-1 showed the most prominent changes across extracellular vesicles with roles in noncanonical signalling. By examining the local and tangential roles of cytokines in stem cells, their roles in signalling and in regenerative mechanisms may be further understood.
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Piccinini, A. M., and K. S. Midwood. "DAMPening Inflammation by Modulating TLR Signalling." Mediators of Inflammation 2010 (2010): 1–21. http://dx.doi.org/10.1155/2010/672395.
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Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.
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Sultan, Salma, Walid Mottawea, JuDong Yeo, and Riadh Hammami. "Gut Microbiota Extracellular Vesicles as Signaling Molecules Mediating Host-Microbiota Communications." International Journal of Molecular Sciences 22, no. 23 (2021): 13166. http://dx.doi.org/10.3390/ijms222313166.
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Over the past decade, gut microbiota dysbiosis has been linked to many health disorders; however, the detailed mechanism of this correlation remains unclear. Gut microbiota can communicate with the host through immunological or metabolic signalling. Recently, microbiota-released extracellular vesicles (MEVs) have emerged as significant mediators in the intercellular signalling mechanism that could be an integral part of microbiota-host communications. MEVs are small membrane-bound vesicles that encase a broad spectrum of biologically active compounds (i.e., proteins, mRNA, miRNA, DNA, carbohydrates, and lipids), thus mediating the horizontal transfer of their cargo across intra- and intercellular space. In this study, we provide a comprehensive and in-depth discussion of the biogenesis of microbial-derived EVs, their classification and routes of production, as well as their role in inter-bacterial and inter-kingdom signaling.
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Wilson, C., N. Vereshchagina, B. Reynolds, D. Meredith, C. A. R. Boyd, and D. C. I. Goberdhan. "Extracellular and subcellular regulation of the PI3K/Akt cassette: new mechanisms for controlling insulin and growth factor signalling." Biochemical Society Transactions 35, no. 2 (2007): 219–21. http://dx.doi.org/10.1042/bst0350219.
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The PI3K (phosphoinositide 3-kinase)/Akt (also called protein kinase B) signalling cassette plays a central role in the response to growth factors, particularly insulin-like molecules, and its misregulation is a characteristic feature of diabetes and many forms of human cancer. Recent molecular genetic studies initiated in the fruitfly, Drosophila melanogaster, have highlighted two new cell-type-specific mechanisms regulating PI3K/Akt signalling and its downstream effects. First, the cellular response to this cassette is modulated by several classes of cell-surface transporters and sensors, suggesting an important role for extracellular nutrients in insulin-sensitivity. Secondly, various cell types show a markedly different subcellular distribution of the activated kinase Akt, influencing the cellular functions of this molecule. These findings reveal new mechanisms by which processes such as growth, lipogenesis and insulin resistance can be differentially regulated and may suggest novel strategies for treating insulin-linked diseases.
Dissertations / Theses on the topic "Extracellular signalling molecules"
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Davidson, David 1963. "Interactive signalling by growth factors and extracellular matrix molecules in cartilage development and metabolism." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102493.
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Articular cartilage reduces friction and absorbs shock protecting the moving ends of bones from damage during normal physical activity. These mechanical properties of cartilage result from the physiological activities of chondrocytes, the phenotypically unique cells that produce and maintain the cartilage matrix. The behaviour of these cells is controlled by extracellular milieu components including: matrix molecules, growth factors, calcium and phosphorus. The interaction of these signals maintains the homeostatic balance between anabolism and catabolism in healthy articular cartilage. Unimpeded imbalances between these processes result in disease states such as Osteoarthritis. In this thesis work the specific and combined effects of PTHrP, FGF, calcium and phosphate signalling on cartilage metabolism were studied. PTHrP was shown to localize to the cell nucleus and under conditions of stress prevented cells from progressing in the cell cycle by inhibiting ribosome biogenesis. Furthermore, it was shown that the expression of the phosphate transporter GLVR-1 was inhibited by the presence of PTHrP in a high stress growth environment. Inhibiting the expression of this receptor effectively prevented intracellular accumulation of phosphate and as a result inhibited chondrocyte differentiation processes. Observation of PTHrP -/-/FGFR3-/- double knockout mice showed a dominant role for PTHrP in promoting chondrocyte proliferation, preventing apoptosis and inhibiting terminal differentiation. In contrast, FGFR3 promoted terminal differentiation and apoptosis in the absence of PTHrP. Additionally, studies of primary chondrocyte cultures generated from FGFR3-/- and FGFR3+/+ mice demonstrated impaired mitogenic response and decreased production of collagen II and proteoglycan in response to FGF18 stimulation in the presence of FGFR3, thus, identifying FGF18 as a selective ligand for FGFR3 in chondrogenic cells.<br>The various studies presented in this thesis show that signals from growth factors, the extracellular matrix and mineral ion components of the extracellular milieu interact to regulate the process of chondrogenesis and identify PTHrP and FGFR3 as potential molecular targets for the bioengineering of cartilage tissue.
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Cotton, Thomas Richard. "The structure of human pro-myostatin and molecular basis of latency." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288560.
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Myostatin is a secreted growth factor of the transforming growth-factor $\beta$ (TGF$\beta$) superfamily, and a powerful negative regulator of muscle mass in vertebrates. As such, there is considerable interest in developing pharmacological agents which inhibit myostatin signalling in order to stimulate muscle growth in the context of pathological muscle wasting. Like other TGF$\beta$ family proteins, myostatin is biosynthesised as an inactive (latent) precursor protein which requires proteolytic processing to liberate the mature bioactive growth factor. To examine the molecular basis of pro-myostatin latency and the mechanism by which it is activated in the extracellular space, I have determined the crystal structure of unprocessed human pro-myostatin and studied the properties of the protein at various stages of activation. Crystallographic analysis of pro-myostatin reveals a unique domain-swapped dimeric structure, with an open V-shaped conformation distinct from the prototypical family member, TGF$\beta$1. Following cleavage of the prodomains by furin, pro-myostatin persists as a stable non-covalent complex which is resistant to the natural inhibitor follistatin and exhibits significantly weaker bioactivity than the mature growth factor. A number of distinct structural features combine to stabilise the interaction between pro and mature domains and in doing so confer latency to the pro-complex. This facilitates a controlled, step-wise process of activation in the extracellular space and contributes to a complex network of regulatory control. The results presented here provide a structural basis for understanding the effect of natural polymorphisms on myostatin function and a starting point for structure-guided development of next generation myostatin inhibitors. As a proof-of-concept, I present preliminary data on prodomain derived stapled peptides as inhibitors of myostatin signalling.
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Larijani, Banafshe. "Role of lipid signalling pathways in an intra and an extracellular phenomenon." 1999. https://scholarworks.umass.edu/dissertations/AAI9950178.
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This dissertation is in two parts. The first part investigates the role of lipid signalling pathways in an intracellular phenomenon i.e. the formation of the nuclear envelope. The second part is a study of lipid signalling pathways in extracellular phenomenon, i.e. HeLa cell adhesion and spreading on a gelatin substrate. The disassembly and formation of the nuclear envelope are crucial steps in the progression of mitosis. Nuclear envelope dynamics involve many steps and since vesicular transport, binding and fusion of vesicles are essential for the formation of the nuclear envelope it was our interest to explore whether there were any parallel pathways, such as found in the secretary pathways, that were also used in the formation of the nuclear envelope. There is little information on the proteins of membrane vesicles that reconstitute the nuclear envelope and practically none about their lipid composition. It was therefore important to determine their lipid structure in order to proceed with investigating whether, during the formation of the nuclear envelope, similar signalling pathways to those in the vesicle trafficking operate. Cytoplasmic membrane vesicle fractions (MVs) from sea urchin eggs which, contribute to the nuclear envelope were studied. The phospholipid composition of the membrane vesicles, MV1, MV2 and MV3 was determined using a novel approach for direct quantification of phospholipids from two-dimensional 31 P-1H nuclear magnetic resonance spectroscopy with isotropic mixing. MV2 and MV3 have similar compositions typical of the ER and the Golgi membranes. However, MV1 is mainly composed of phosphatidylinositol with phosphatidylcholine being the minor phospholipid present in MV1. Furthermore, we determined that phosphatidylinositol specific phospholipase C (PI-PLC) promoted nuclear envelope formation. However, in the absence of MV1, PI-PLC, did not induce nuclear envelope formation. Inhibition of membrane vesicle fusion in a dose dependent manner, by wortmannin (a specific inhibitor of the PI-3kinase pathway) suggested that the PI-3 kinase branch of the phosphatidylinositol pathway may be involved in the formation of the nuclear envelope. These experiments indicate that the inositol phospholipid pathways, as in constitutive membrane trafficking, are also involved in the formation of the nuclear envelope. Furthermore, it is the first time that a biological membrane, MV1, with such an unusual composition has been reported and that it has been demonstrated the phosphatidylinositol hydrolysis is involved in the formation of the nuclear envelope. In the second part the goal was to determine which lipoxygenase metabolites were involved in facilitating HeLa cell adhesion and spreading to a gelatin substrate. Reverse phase HPLC methods demonstrated that HeLa cell homogenates converted arachidonic acid into 12-, 15- and 5-hydroperoxyeicosatetraenoic (HETEs), indicating that 12, 15 and 5 lipoxygensases are active in HeLa cells. In order to investigate which lipoxygenase pathway are required to induce cell spreading the lipoxygenase pathway was inhibited by 25uM nordihydroguaiaretic acid (NDGA), a specific inhibitor of the lipoxygenases and MK866, a specific inhibitor of leukotriene biosynthesis. The effect of the different enantiomers of 12-BETE and 15-HETE on the reversal of NDGA inhibition was determined. The leukotrienes that overcome the inhibition of cell spreading by NDGA and MK866 were also determined. It can be concluded that 12,15 and 5 lipoxygenase enzymes are present and active in HeLa cells; and 12-HETE, 15-HETE, leukotrienes LTB4, LTD4 and LTC4 play an active role in HeLa cell spreading on a gelatin substrate.
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Czopka, Tim [Verfasser]. "Cellular and molecular analysis of extracellular matrix induced signalling cues on the differentiation of oligodendrocytes / by Tim Czopka." 2009. http://d-nb.info/997294957/34.
Full textBooks on the topic "Extracellular signalling molecules"
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Kühn, Wolfgang, and Gerd Walz. The molecular basis of ciliopathies and cyst formation. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0303.
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Abnormalities of the cilium, termed ‘ciliopathies’, are the prime suspect in the pathogenesis of renal cyst formation because the gene products of cystic disease-causing genes localize to them, or near them. However, we only partially understand how cilia maintain the geometry of kidney tubules, and how abnormal cilia lead to renal cysts, and the diverse range of diseases attributed to them. Some non-cystic diseases share pathology of the same structures. Although still incompletely understood, cilia appear to orient cells in response to extracellular cues to maintain the overall geometry of a tissue, thereby intersecting with the planar cell polarity (PCP) pathway and the actin cytoskeleton. The PCP pathway controls two morphogenetic programmes, oriented cell division (OCD) and convergent extension (CE) through cell intercalation that both seem to play a critical role in cyst formation. The two-hit theory of cystogenesis, by which loss of the second normal allele causes tubular epithelial cells to form kidney cysts, has been largely borne out. Additional hits and influences may better explain the rate of cyst formation and inter-individual differences in disease progression. Ciliary defects appear to converge on overlapping signalling modules, including mammalian target of rapamycin and cAMP pathways, which can be targeted to treat human cystic kidney disease irrespective of the underlying gene mutation.
Book chapters on the topic "Extracellular signalling molecules"
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Chabannon, Christian, and Chiara Bonini. "Structure of and Signalling Through Chimeric Antigen Receptor." In The EBMT/EHA CAR-T Cell Handbook. Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-94353-0_1.
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AbstractChimeric antigen receptor (CAR) is a synthetic transmembrane protein expressed at the surface of immune effector cells (IECs) that are reprogrammed either in vitro or in vivo (June et al. 2018; June and Sadelain 2018). Techniques for genetic engineering of autologous or allogeneic IECs are described in the next chapter. The synthetic CAR incorporates several functional domains. The extracellular domain is composed of a single chain variable fragment (ScFV) of immunoglobulin and recognizes the “tumour” antigen. The clinical relevance of the selected tumour antigen—with a view to minimize “on-target/off-tumour” side effects—is discussed in the third chapter of this section. Bispecific and trispecific CARs are currently being evaluated in preclinical and early clinical trials (Bielamowicz et al. 2018; Shah et al. 2020). The use of an immunoglobulin domain as the ligand of the target antigen means that recognition is not restricted to HLA antigens and that CAR-T cells are universally applicable as opposed to T cell receptor (TCR) transgenic T cells that recognize antigenic peptides presented in the context of a defined major histocompatibility complex (MHC), limiting clinical applications to subsets of patients with defined HLA typing. The intracellular domain is composed of the intracellular domain of the zeta chain of the CD3 component of the TCR, which will trigger signalling when the CAR engages the targeted ligand. The transmembrane region links the two extracellular and intracellular domains through the cell membrane and plays an important role in determining the conformation and flexibility of the CAR and its ability to efficiently bind the targeted antigen/epitope. Association of only these three functional domains characterized first generation CARs, as described in the original publications (Kuwana et al. 1987; Eshhar et al. 1993). However, full activation of T cells requires the addition of one (second generation CARs) or two (third generation CARs) domains from costimulatory molecules, such as CD28, 4-1BB/CD137, or OX40/CD134, that provide the T cell costimulatory signal. Currently approved CAR-T cells are second generation CAR-T cells; as an illustration, the CAR in tisagenlecleucel contains a 4-1BB domain, while the CAR in axicabtagene ciloleucel contains a CD28 domain. The nature of the costimulatory domain influences the ability of CAR-T cells to expand or persist (limit T cell exhaustion) in vivo after infusion into the patient, although it is unclear how this translates clinically and affects disease control, occurrence of adverse events, and overall survival due to the lack of head-to-head comparison between approved products. Finally, fourth generation CAR-T cells have been developed for preclinical projects. These cells, named armoured CAR cells or T cells redirected for universal cytokine-mediated killing (TRUCKS), encode not only a CAR (usually with one costimulatory domain, such as in second generation CARs) but also a cytokine, interleukin, pro-inflammatory ligand, or chemokine that will counteract the immune suppressive microenvironment that prevails in most solid tumours (Eshhar et al. 1993; Chmielewski and Abken 2015).
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Hyde, Caroline A. C., Philipp Berger, and Kurt Ballmer-Hofer. "Finding New Partnerships: The Function of Individual Extracellular Receptor Domains in Angiogenic Signalling by VEGF Receptors." In Molecular Mechanisms of Angiogenesis. Springer Paris, 2014. http://dx.doi.org/10.1007/978-2-8178-0466-8_3.
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Wang, Qiuyu, Chris Smith, and Emma Davis. "Cell signalling." In Thrive in Cell Biology. Oxford University Press, 2013. http://dx.doi.org/10.1093/hesc/9780199697328.003.0015.
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This chapter explains that cells communicate with one another using chemical or electrical signals that activate complex signalling pathways. It describes the cells of animals and plants which communicate using extracellular messengers or ligands, noting that local communication occurs by secreting and receiving local-acting extracellular messengers, while long-distance signalling between cells uses hormones. It also outlines a variety of biological molecules that function as extracellular messengers or ligands, which include hormones, derivatives of vitamins A and D, growth factors and cytokines, eicosanoids, and neurotransmitters. The chapter explores the common features of receptors of signal molecules, such as binding a signalling molecule and receptor. It covers signal transduction pathways, which are one of the many ways organisms coordinate their activities.
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Hancock, John T. "Extracellular signals: hormones, cytokines and growth factors." In Cell Signalling. Oxford University Press, 2016. http://dx.doi.org/10.1093/hesc/9780199658480.003.0004.
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This chapter concentrates on the release and detection of extracellular signalling molecules, such as hormones, cytokines, and growth factors. It argues that such molecules are often released some considerable distance from their point of action and generally have an effect over a relatively long time-scale with an unspecific transport to the site of action. The chapter then describes hormones as a diverse group of molecules, highlighting that they may be small and water-soluble peptides or lipophilic molecules. It also considers a diverse group of chemicals: plant hormones and a group of peptides—cytokines. Towards the end, the chapter explores the nature of growth factors—molecules involved in the regulation of growth and differentiation of cells. It also considers other extracellular signals like the pheromones, energy storage compound ATP, and a compound usually associated with intracellular signalling, cAMP.
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Mita, Monica M., and Eric K. Rowinsky. "The RAS pathway-a target for anticancer therapy." In Cancer biotherapy. Oxford University PressOxford, 2006. http://dx.doi.org/10.1093/oso/9780198566311.003.0006.
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Abstract Cellular signalling is critical for embryonic development, tissue differentiation, and cellular response to the environment. The complex signalling network is initiated in large part by extracellular ligands, including growth factors and other various stimuli, which interact with membrane receptors and then activate a cascade of intracellular molecules known as secondary messengers that ultimately are responsible for the cellular response. De-regulated cellular signalling is a common feature of cancer cells, which leads to uncontrolled proliferation and increased survival. Identification of the molecular abnormalities in cancer cells, particularly key proteins that play a role in abnormal cell proliferation, have led to the development of anticancer strategies that disrupt the synthesis or function of these proteins. As a large body of data about the cellular signalling network is accumulating, the complexities related to these strategies are being recognised and it is becoming increasingly clear that the redundancies in cellular signalling are very important in cancer cells, making approaches to therapy that involve any single pathway more challenging.
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Das, Theerthankar, and Brandon C. Young. "Biofilm Formation by Pathogenic Bacteria: The Role of Quorum Sensing and Physical - Chemical Interactions." In Focus on Bacterial Biofilms [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106686.
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Pathogenic bacteria cause infectious diseases, mainly when the host (humans, animals, and plants) are colonised by bacteria, especially in its biofilm stage, where it is known to cause chronic infections. Biofilms are associated with resistance to antimicrobial agents, including antibiotics, antiseptics, detergents, and other therapeutic approaches. Antimicrobial resistance (AMR) is one of the biggest public health challenges of our time and is termed a ‘silent pandemic’ by the United Nations. Biofilm formation, pathogenicity and the associated AMR are regulated through a bacterial cell-to-cell communication system termed “Quorum Sensing (QS)’. As the bacterial cells sense the fluctuations in their population, they biosynthesise and secrete the signalling molecules called autoinducers (AI). In gram-negative, the signalling molecules are primarily homoserine lactones (AHL) whereas in gram-positive the signalling molecules are autoinducing peptides. The AI binds to receptor and regulator proteins in the bacterial cells to activate the complete QS system, which controls the regulations of various genes that are essential for the biosynthesis of virulence factors, extracellular biopolymers (EPS) production, biofilm formation and bacterial fitness.
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Humphries, Martin J., and Robert C. Liddington. "Molecular basis of integrin-dependent cell adhesion." In Protein-Protein Recognition. Oxford University PressOxford, 2000. http://dx.doi.org/10.1093/oso/9780199637614.003.0004.
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Abstract The integrins are a family of heterodimeric (α β) plasma membrane proteins that bind the extracellular matrix or counter-receptors on other cells (1). They transduce bidirectional signals across the plasma membrane that are critical to many biological processes, including embryonic cell migration, wound healing, and the immune response. In pathogenic states they play an essential role in tumour metastasis and angiogenesis. The adhesiveness of integrins’ extracellular domains is allosterically controlled by binding events in their cytoplasmic domains that trigger conformational changes across the plasma membrane (‘inside-out’ signalling). Under some conditions it is ligand binding to the extracellular domains that triggers an intracellular signal (‘outside-in’ signalling). There are two mechanisms by which integrins could change the adhesiveness of cells, which are not necessarily exclusive. ‘Affinity’ changes caused by conformational changes in individual integrin molecules are believed to be responsible for both the initial rapid and reversible change in the affinity of platelets for damaged blood vessels and of leucocytes for sites of inflammation (2). ‘Avidity’ changes brought about by the synergistic effect of multiple clustered integrins on the cell surface binding to clustered or polyvalent ligands are thought to play a role in the stable attachment of cells to the extracellular matrix (ECM) (3).
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Naylor, M. S., and F. R. Balkwill. "The role of cytokines in tumour progression." In Cell Proliferation in Cancer. Oxford University PressOxford, 1995. http://dx.doi.org/10.1093/oso/9780198547914.003.0005.
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Abstract Cytokines make up the fourth major class of soluble intercellular signalling mole cules alongside hormones, neurotransmitters, and prostaglandins/leukotrienes. They possess a number of common features despite the variety of molecular structures and properties. Cytokines are all polypeptides of low molecular weight (generally less than 80 kDa) that bind to high affinity cell surface receptors and cause changes in macromoleculer synthesis in target cells. Cytokines may act in a paracrine, autocrine (including intracellular autocrine loops), and juxtacrine manner (i.e., cytokines expressed on the surface of one cell may affect specific receptors on adjacent cells) at picomolar concentrations, leading to alterations in cell behaviour. Most cytokines are pleiotropic and have multiple biological activities regulating cell proliferation, differentiation, and cell death. Their production in vivo is normally transient and tightly controlled. They are produced by more than one cell type, have overlapping biological activities, and generally act over short distances. Most mammalian cells secrete a range of cytokines and respond to a variety of these molecules (Table 5.1). Cytokines are thought to co-ordinate local tissue organization. This effect is ensured by the short half-life of these molecules in the extracellular space, and by their association with extracellular matrix elements and various binding proteins.
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Bos, Johannes L. "Ras." In GTPases. Oxford University PressOxford, 2000. http://dx.doi.org/10.1093/oso/9780199637454.003.0003.
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Abstract Ras is a molecular switch that controls the transduction of signals from cell-surface receptors to intracellular targets (Fig. la). Like all GTPases, the switch mechanism consists of activation by exchange of bound GDP for GTP, and inactivation by hydrolysis of GTP into GDP. Ras achieved notoriety in the 1980s with the discovery that 15% of all human tumours contain a point mutation in one of the three Ras genes. The resulting mutant protein is unable to hydrolyse bound GTP and therefore remains constitutively in the active conformation. As a consequence, cells experience a continuous growth-promoting signal in the absence of extracellular cues. Ras has been studied extensively and much is known about mechanisms of activation and of downstream signalling. In most cells, Ras is activated in response to a variety of extracellular signals, which stimulate tyrosine kinases either directly or indirectly. In its GTP-bound state, Ras associates with one of several effector molecules, most notably members of the Raf family, the RalGDS family, or PI3K. The biological consequences of these interactions depend greatly on the cell type and on the context of other signalling events. In addition, poorly understood parameters, such as the timing and intensity of the signal, may determine the ultimate response. Interestingly, Ras is highly conserved both in structure and function during evolution. In the yeast Saccharomyces cerevisiae, Ras is involved in nutrient response, in Schizosaccharomyces pombe Ras regulates the pheromone response in mating, and in the nematode Caenorhabditis elegans and the fruitfly Drosophila Ras is a key component of numerous developmental processes. This chapter will provide a background to Ras and present some current ideas about the molecular mechanisms of Ras signalling.
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Hepler, John R., and Julie A. Saugstad. "Protein regulators of GPCR function." In Understanding G protein-coupled receptors and their role in the CNS. Oxford University PressOxford, 2002. http://dx.doi.org/10.1093/oso/9780198509165.003.0007.
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Abstract As described in previous chapters many extracellular ligands such as neurotransmitters, hormones, cytokines, and sensory input rely upon G protein-coupled receptors (GPCRs) and linked signalling pathways to exert their actions at target cells. The established dogma is that these extracellular stimuli utilize a receptor, a heterotrimeric guanine nucleotide binding protein (G protein αβγ subunit complex), and downstream effector proteins to transmit their signals across the plasma membrane (Hepler and Gilman 1992; Clapham and Neer 1997; Hamm 1998). Specifically, agonist occupancy of GPCRs causes exchange of GTP for GDP on Gα that activates Gα and stimulates its dissociation from the Gβγ complex. Free Gα -GTP and Gβγ then directly regulate the activity of well-defined effector proteins (e.g. adenylyl cyclases, phospholipases, ion channels) that, in the case of enzyme targets, generate second messenger molecules. In this model, second messengers activate signalling cascades that account for the many cellular actions initiated by the activated receptor. However, a wealth of new information highlights the limitations of this model and suggests that GPCRs utilize a growing list of additional protein binding partners to carry out their cellular actions (Bockaert and Pin 1999; Hall et al . 1999a )