Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown that FGF (basic or acidic) is mitogenic for quiescent hamster lung fibroblasts (CCL39 line). It is active alone but is much more efficient in synergistic combinations with G-protein-activating agents. When used alone, FGF appears to exert its mitogenic effects without involving any of the major G-protein-mediated signaling pathways. It causes no significant hydrolysis of phosphoinositides, it does not alter the activity of adenylate cyclase, and its mitogenicity is insensitive to pertussis toxin. It therefore seems likely that all pleiotropic actions of FGF are primarily mediated by the intrinsic protein tyrosine kinase of its receptors. However, FGF, acting through its receptor tyrosine kinase, and thrombin, acting through G-protein-coupled receptors, induce a common set of early responses detected within seconds or minutes at the level of membranes, cytoplasm, and nuclei. Typical examples of early responses are activation of Na/H antiporter and Na/K/Cl cotransporter, phosphorylation of ribosomal protein S6, and increased transcription of early-immediate genes (c-fos, c-jun, and c-myc). Not only various classes of growth factors acting via distinct transducing mechanisms activate common targets, but also their synergistic effects on reinitiation of DNA synthesis is reflected on the early responses. How does the coordination of these signaling events take place? A partial answer to this question is illustrated in Figure 6 in which "switch kinases" play the role of integrators of multiple extracellular signals. Raf and, perhaps more convincingly, MAP kinases that are activated by dual phosphorylation on tyrosine and threonine residues are potential good candidates for this integration. This hypothetical scheme could therefore explain, in part, the coordination and the synergy commonly observed in the mitogenic response. The synergy could be generated at the level of MAP kinases simply by dual activating phosphorylations. With the recent cloning of MAP kinases, these questions will be more easily addressed. Another important gap that will have to be filled in future studies is the identification of all the members of the kinase cascade. When used in synergistic combinations with G-protein-activating agents, FGF does exert in contrast some effects on the G-protein-mediated pathways. It potentiates the G-protein-mediated activations of both PIP2-PLC and adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mitogenic effects of fibroblast growth factors in cultured fibroblasts. Interaction with the G-protein-mediated signaling pathways. 166 81

Treatment of cultured astrocytes from 2-day-old rat cerebral hemispheres with insulin, somatomedin C (IGF1), thrombin and acidic or basic fibroblast growth factors promoted a rapid activation of a cytosolic protein kinase (S6 kinase) which phosphorylates ribosomal protein S6. The phorbol ester (TPA) also triggered a rapid increase in S6 kinase activity. Two agonists of adenylate cyclase activity (forskolin and isoproterenol) and the cyclic AMP analog (dibutyryl cAMP) also stimulated the same S6 kinase. These observations support the idea that several pathways might promote the activation of the same entity that is regarded as one of the primary targets of signals elicited by growth factors.
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PMID:[A model for studying the transmission of information produced by certain growth factors: activation mechanisms of S6 kinase in cultured astrocytes]. 262 75

Xenopus oocytes are stimulated to undergo meiotic cell division in response to several types of mitogenic stimuli. Agents that reduce cAMP levels induce cell division in oocytes, and this occurs due to inhibition of adenylate cyclase with progesterone as well as by activation of phosphodiesterase with insulin. Phorbol esters and microinjected protein kinase C also promote cell division, implicating phospholipid breakdown as another signalling pathway competent to induce proliferation in this system. A third signalling pathway is via the tyrosine kinase activity of the insulin receptor. A proximal activation of a ribosomal protein S6 kinase by insulin has provided insight into the regulation of this pathway. All three of these signal transduction pathways lead to the activation of a cytoplasmic protein able to induce nuclear breakdown, chromosome condensation and spindle formation in vivo and in vitro. This protein, known as maturation-promoting factor, is associated with changes in protein phosphorylation on both serine and tyrosine residues. These results support a model in which signal transduction by different pathways activates a common cell cycle control element that regulates the G2----M transition via changes in protein phosphorylation.
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PMID:Mitogenic signalling and protein phosphorylation in Xenopus oocytes. 283 Dec 61

Xenopus oocyte maturation is a model system for studying the control of cell proliferation and the regulation of the cell cycle. Addition of progesterone or insulin to oocytes releases a G2 block and stimulates progression through meiosis to an unfertilized egg. The release of the G2 block is a consequence of a decrease in cAMP mediated entirely or in part by an inhibition of adenylate cyclase. The mechanism of cyclase inhibition involves a membrane steroid receptor controlling the rate of guanine nucleotide exchange. Subsequent events include an increase in intracellular pH and the phosphorylation of ribosomal protein S6. The latter event may play a role in translational control of maturation. Late events in maturation involve the appearance of the maturation-promoting factor (MPF), a cytoplasmic protein responsible for causing nuclear envelope breakdown, chromosome condensation, and spindle formation. MPF oscillates in meiotic and mitotic cell cycles. The events caused by MPF can now be obtained in crude extracts with retention of cell cycle control by calcium, providing a framework for rapid progress in characterizing MPF and its regulation.
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PMID:Regulation of amphibian oocyte maturation. 299 Jul 31

The present review is focused on the exocrine pancreas and liver where the only known effector mechanism of VIP is the activation of adenylate cyclase in plasma membranes. A two-state model of activation-deactivation of the enzyme visualizes the participation of VIP receptors and Ns, the guanyl nucleotide stimulatory protein of adenylate cyclase. In the rat pancreas, VIP and GRF receptors are indistinguishable and disulfide bridges influence their functional integrity. The antagonism of VIP and somatostatin perhaps requires, at the adenylate cyclase level, the contribution of Ni, the guanyl nucleotide inhibitory protein. The potentiation of VIP by various stimulants acting on Ca2+ movements may rely on later events, e.g., on a concerted activation of protein kinases. When comparing quantitatively peptide binding to receptors with adenylate cyclase activation, cyclic AMP levels and amylase secretion, a tool is at hand to tailor synthetic agonists and antagonists of VIP, with appropriate changes in the N-terminal moiety of the peptide (a good agonist allows efficient coupling of receptors to the adenylate cyclase system). Apart from stimulus-secretion coupling, VIP may influence protein synthesis in the rat pancreas, through the phosphorylation of ribosomal protein S6, and may alter the activity of the endoplasmic reticulum via the phosphorylation of Mr = 21 kDa and Mr = 25 kDa proteins. In rat liver membranes, high affinity VIP receptors are specifically labelled with 125I-helodermin and are coupled to adenylate cyclase (at variance with low affinity VIP receptors). These receptors are highly responsive to divalent cations and to guanyl nucleotides.
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PMID:Effector mechanisms of peptides of the VIP family. 301 87

The insect prothoracic glands are the source of steroidal molting hormone precursors and the glands are stimulated by a brain neuropeptide, prothoracicotropic hormone (PTTH). Previous work from this laboratory revealed that PTTH acts via a cascade including Ca2+/calmodulin activation of adenylate cyclase, protein kinase A, and the subsequent phosphorylation of a 34 kDa protein (p34) hypothesized, but not proven, to be the S6 protein of the 40S ribosomal subunit. The immunosuppressive macrolide, rapamycin, is a potent inhibitor of cell proliferation, a signal transduction blocker, and also prevents ribosomal S6 phosphorylation in mammalian systems. We demonstrate here that rapamycin inhibited PTTH-stimulated ecdysteroidogenesis in vitro by the prothoracic glands of the tobacco hornworm, Manduca sexta, with half-maximal inhibition at a concentration of about 5 nM. At concentrations above 5 nM, there was a 75% inhibition of ecdysteroid biosynthesis. Similar results were observed with the calcium ionophore (A23187), a known stimulator of ecdysteroidogenesis. Most importantly, the inhibition of ecdysteroid biosynthesis was accompanied by the specific inhibition of the phosphorylation of p34, indicating that p34 indeed is ribosomal protein S6. In vivo assays revealed that injection of rapamycin into day 6 fifth instar larvae resulted in a decreased hemolymph ecdysteroid titer and a dose-dependent delay in molting and metamorphosis. When S6 kinase (S6K) activity was examined using rapamycin-treated prothoracic glands as the enzyme source and a synthetic peptide (S6-21) or a 40S ribosomal subunit fraction from Manduca tissues as substrate, the date revealed that rapamycin inhibited S6K activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:S6 phosphorylation results from prothoracicotropic hormone stimulation of insect prothoracic glands: a role for S6 kinase. 792 36