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Cells Oct 2020The cyclic nucleotides 3',5'-adenosine monophosphate (cyclic AMP) signalling system underlies the control of many biological events and disease processes in man. Cyclic...
The cyclic nucleotides 3',5'-adenosine monophosphate (cyclic AMP) signalling system underlies the control of many biological events and disease processes in man. Cyclic AMP is synthesised by adenylate cyclase (AC) enzymes in order to activate effector proteins and it is then degraded by phosphodiesterase (PDE) enzymes. Research in recent years has identified a range of cell-type-specific cyclic AMP effector proteins, including protein kinase A (PKA), exchange factor directly activated by cyclic AMP (EPAC), cyclic AMP responsive ion channels (CICs), and the Popeye domain containing (POPDC) proteins, which participate in different signalling mechanisms. In addition, recent advances have revealed new mechanisms of action for cyclic AMP signalling, including new effectors and new levels of compartmentalization into nanodomains, involving AKAP proteins and targeted adenylate cyclase and phosphodiesterase enzymes. This Special Issue contains 21 papers that highlight advances in our current understanding of the biology of compartmentlised cyclic AMP signalling. This ranges from issues of pathogenesis and associated molecular pathways, functional assessment of novel nanodomains, to the development of novel tool molecules and new techniques for imaging cyclic AMP compartmentilisation. This editorial aims to summarise these papers within the wider context of cyclic AMP signalling.
Topics: Adenylyl Cyclases; Cell Adhesion Molecules; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Guanine Nucleotide Exchange Factors; Humans; Ion Channels; Signal Transduction
PubMed: 33053803
DOI: 10.3390/cells9102274 -
Journal of Hematology & Oncology Jan 2024Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which... (Review)
Review
Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
Topics: Humans; Guanine Nucleotide Exchange Factors; Tumor Microenvironment; Signal Transduction; Neoplasms; Cyclic AMP
PubMed: 38233872
DOI: 10.1186/s13045-024-01524-x -
Cold Spring Harbor Perspectives in... May 2011The protein processing and trafficking function of the Golgi is intimately linked to multiple intracellular signaling pathways. Assembly of Golgi trafficking structures... (Review)
Review
The protein processing and trafficking function of the Golgi is intimately linked to multiple intracellular signaling pathways. Assembly of Golgi trafficking structures and lipid sorting at the Golgi complex is controlled and coordinated by specific phosphoinositide kinases and phosphatases. The intra-Golgi transport machinery is also regulated by kinases belonging to several functionally distinct families, for example, MAP kinase signaling is required for mitotic disassembly of the Golgi. However, the Golgi plays an additional, prominent role in compartmentalizing other signaling cascades that originate at the plasma membrane or at other organelles. This article summarizes recent advances in our understanding of the signaling network that converges at the Golgi.
Topics: Biological Transport; Cell Enlargement; Cell Membrane; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Golgi Apparatus; Lipid Metabolism; Phosphatidylinositols; Signal Transduction
PubMed: 21454247
DOI: 10.1101/cshperspect.a005314 -
Advances in Clinical and Experimental... Nov 2022The shortcomings of mRNA sequencing in explaining biological functions have resulted in proteomics gradually becoming a hotspot for research. However, the function of... (Review)
Review
The shortcomings of mRNA sequencing in explaining biological functions have resulted in proteomics gradually becoming a hotspot for research. However, the function of proteins becomes complicated as a result of post-translational modifications (PTMs) such as phosphorylation, glycosylation, acetylation, etc. Post-translational modifications do not change the physicochemical properties such as charge and solubility of the proteins, but they can have significant consequences on disease initiation in living organisms. The cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) is an important transcription regulator in eukaryotic cells. It is involved in the development of neurodegenerative diseases, diabetic complications, tumorigenesis, and neurogenesis. Previously, researchers have paid much more attention to the phosphorylation modification of CREB. However, it seems that the functional regulation-mediated glycosylation modification of CREB was just beginning to be understood. In this review, the current studies and most updated insights on how the glycosylation modification of CREB affects targeted gene expression and disease development will be comprehensively discussed. We hope to further evaluate the role of CREB glycosylation on the regulation of gene function.
Topics: Humans; Cyclic AMP Response Element-Binding Protein; Cyclic AMP; Glycosylation; Phosphorylation; Gene Expression Regulation
PubMed: 35951625
DOI: 10.17219/acem/151026 -
FEBS Letters Sep 1983The role of cyclic AMP and calcium in the control of normal and tumour cell growth is considered in relation to the question whether cyclic AMP is a true mitogen or... (Review)
Review
The role of cyclic AMP and calcium in the control of normal and tumour cell growth is considered in relation to the question whether cyclic AMP is a true mitogen or co-mitogen. It is proposed that cyclic AMP normally controls the cell cycle at a point in G1 phase only by virtue of its ability to exclude calcium required by cells to progress past this point into S phase. Therefore increased influx of calcium by other routes induced by various factors can bypass the inhibitory effect of cyclic AMP and stimulate growth. In these circumstances cyclic AMP or calcium may or may not facilitate further progress into S phase according to the metabolic requirements of individual cells. The relevance to cancer cells is considered.
Topics: Animals; Calcium; Cell Cycle; Cell Division; Cyclic AMP; Humans; Kinetics; Mitogens; Neoplasms
PubMed: 6309571
DOI: 10.1016/0014-5793(83)80719-4 -
Research in Microbiology 1996
Review
Topics: Carbohydrate Metabolism; Cyclic AMP; Cyclic AMP Receptor Protein; Depression, Chemical; Escherichia coli; In Vitro Techniques
PubMed: 9084758
DOI: 10.1016/0923-2508(96)84002-2 -
Microbiological Reviews Sep 1994A few hours after the onset of starvation, amoebae of Dictyostelium discoideum start to form multicellular aggregates by chemotaxis to centers that emit periodic cyclic... (Review)
Review
A few hours after the onset of starvation, amoebae of Dictyostelium discoideum start to form multicellular aggregates by chemotaxis to centers that emit periodic cyclic AMP signals. There are two major developmental decisions: first, the aggregates either construct fruiting bodies directly, in a process known as culmination, or they migrate for a period as "slugs." Second, the amoebae differentiate into either prestalk or prespore cells. These are at first randomly distributed within aggregates and then sort out from each other to form polarized structures with the prestalk cells at the apex, before eventually maturing into the stalk cells and spores of fruiting bodies. Developmental gene expression seems to be driven primarily by cyclic AMP signaling between cells, and this review summarizes what is known of the cyclic AMP-based signaling mechanism and of the signal transduction pathways leading from cell surface cyclic AMP receptors to gene expression. Current understanding of the factors controlling the two major developmental choices is emphasized. The weak base ammonia appears to play a key role in preventing culmination by inhibiting activation of cyclic AMP-dependent protein kinase, whereas the prestalk cell-inducing factor DIF-1 is central to the choice of cell differentiation pathway. The mode of action of DIF-1 and of ammonia in the developmental choices is discussed.
Topics: Ammonia; Animals; Cyclic AMP; Dictyostelium; Gene Expression Regulation, Developmental; Models, Biological; Signal Transduction
PubMed: 7968918
DOI: 10.1128/mr.58.3.330-351.1994 -
Proceedings of the National Academy of... Apr 2021bis-(3',5')-cyclic diadenosine monophosphate (c-di-AMP) is a second messenger with roles in virulence, cell wall and biofilm formation, and surveillance of DNA integrity...
bis-(3',5')-cyclic diadenosine monophosphate (c-di-AMP) is a second messenger with roles in virulence, cell wall and biofilm formation, and surveillance of DNA integrity in many bacterial species, including pathogens. Strikingly, it has also been proposed to coordinate the activity of the components of K homeostasis machinery, inhibiting K import, and activating K export. However, there is a lack of quantitative evidence supporting the direct functional impact of c-di-AMP on K transporters. To gain a detailed understanding of the role of c-di-AMP on the activity of a component of the K homeostasis machinery in , we have characterized the impact of c-di-AMP on the functional, biochemical, and physiological properties of KhtTU, a K/H antiporter composed of the membrane protein KhtU and the cytosolic protein KhtT. We have confirmed c-di-AMP binding to KhtT and determined the crystal structure of this complex. We have characterized in vitro the functional properties of KhtTU and KhtU alone and quantified the impact of c-di-AMP and of pH on their activity, demonstrating that c-di-AMP activates KhtTU and that pH increases its sensitivity to this nucleotide. Based on our functional and structural data, we were able to propose a mechanism for the activation of KhtTU by c-di-AMP. In addition, we have analyzed the impact of KhtTU in its native bacterium, providing a physiological context for the regulatory function of c-di-AMP and pH. Overall, we provide unique information that supports the proposal that c-di-AMP is a master regulator of K+ homeostasis machinery.
Topics: Bacillus subtilis; Bacterial Proteins; Binding Sites; Cyclic AMP; Homeostasis; Potassium; Potassium-Hydrogen Antiporters; Protein Binding
PubMed: 33790011
DOI: 10.1073/pnas.2020653118 -
Structure (London, England : 1993) Dec 2009GAF domains regulate the catalytic activity of certain vertebrate cyclic nucleotide phosphodiesterases (PDEs) by allosteric, noncatalytic binding of cyclic nucleotides.... (Review)
Review
GAF domains regulate the catalytic activity of certain vertebrate cyclic nucleotide phosphodiesterases (PDEs) by allosteric, noncatalytic binding of cyclic nucleotides. GAF domains arranged in tandem are found in PDE2, -5, -6, -10, and -11, all of which regulate the cellular concentrations of the second messengers cAMP and/or cGMP. Nucleotide binding to GAF domains affects the overall conformation and the catalytic activity of full-length PDEs. The cyclic nucleotide-bound GAF domains from PDE2, -5, -6, and -10 all adopt a conserved fold but show subtle differences within the binding pocket architecture that account for a large range of nucleotide affinities and selectivity. NMR data and details from the structure of full-length nucleotide-free PDE2A reveal the dynamic nature and magnitude of the conformational change that accompanies nucleotide binding. The discussed GAF domain structures further reveal differences in dimerization properties and highlight the structural diversity within GAF domain-containing PDEs.
Topics: Amino Acid Sequence; Binding Sites; Cyclic AMP; Cyclic GMP; Dimerization; Models, Molecular; Molecular Sequence Data; Phosphoric Diester Hydrolases; Protein Conformation; Sequence Homology, Amino Acid
PubMed: 20004158
DOI: 10.1016/j.str.2009.07.019 -
The EMBO Journal Jan 1985By means of a K+-sensitive electrode, the extracellular K+ concentration was monitored in cell suspensions of Dictyostelium discoideum. In aggregative cells the...
By means of a K+-sensitive electrode, the extracellular K+ concentration was monitored in cell suspensions of Dictyostelium discoideum. In aggregative cells the attractant cyclic AMP induced a transient release of K+. The response was detectable within 6-12 s and peaked at 30-40 s. The apparent rate of release amounted to 7 X 10(8)K+ ions per cell per min. Adenosine and 5' AMP, which are chemotactically inactive, did not elicit measurable K+ responses. The cyclic AMP-induced release of K+ depended on the state of differentiation of the cells. In undifferentiated cells cyclic AMP did not cause a measurable K+ release, whereas folic acid, a potent attractant at this cell stage, induced a weak but significant K+ response. The cyclic AMP-induced K+ release in aggregative cells was inhibited by K+-channel blockers such as quinine and tetraethylammonium. In suspensions of differentiated cells free running oscillations of the extracellular K+ concentration were observed. K+ oscillations were related to cyclic AMP oscillations and oscillations of the light-scattering properties of cells. Cells continuously released NH4+; however, cyclic AMP did not induce a measurable change of NH4+ release.
Topics: Ammonia; Calcium; Cyclic AMP; Dictyostelium; Potassium
PubMed: 2990896
DOI: 10.1002/j.1460-2075.1985.tb02314.x