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

The essential CDC25 gene product of Saccharomyces cerevisiae is the most upstream known component of the RAS/adenylate cyclase pathway. Cdc25 is a GTP-exchange protein involved in activating RAS in response to fermentable carbon sources. In this paper it is reported that the Cdc25 protein, in addition to its stimulatory role in the RAS/adenylate cyclase pathway, regulates glucose transport. Continuous culture studies and glucose uptake experiments showed that the cdc25-1 and the cdc25-5 temperature-sensitive mutants exhibit decreased glucose uptake activity at the restrictive temperature under both repressed and derepressed conditions as compared to the wild-type strain. Because the cdc25-1 mutant is not impaired in its cAMP metabolism, it is concluded that this effect on glucose transport is independent of cAMP levels. Furthermore, it is shown that the decrease in glucose uptake activity is not due to a decrease in protein synthesis or to an arrest in the G1 phase of the cell cycle. In addition to a defect in glucose uptake, the cdc25-5 mutant strain exhibited differences in glucose metabolism, probably due to the decreased cAMP level and hence decreased protein kinase A activity. Because the Cdc25 protein is localized at the membrane, these results indicate that Cdc25 is directly involved in glucose transport and may be in direct contact with the glucose transporters.
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PMID:The Cdc25 protein of Saccharomyces cerevisiae is required for normal glucose transport. 875 40

Random RAS2 mutants of Saccharomyces cerevisiae were screened for activating traits. A total of 69 distinct mutations were identified, affecting 44 different amino acid residues. Many activated alleles do not bypass the requirement for the nucleotide exchange factor, CDC25, nor is the severity of RAS2 phenotypic traits strictly correlated with the capacity to bypass CDC25. In vivo interactions of mutant RAS2 proteins with RAS effectors (adenylate cyclase and RAF), CDC25 and GTPase activating proteins (IRA2 and NF1) were assayed to assess how the various amino acid substitutions influence interactions with regulatory and target proteins of RAS. Nearly all activated RAS2 proteins were observed to interact better with adenylate cyclase and RAF, although some distinct differences were found. Several amino acid substitutions that reduce the affinity of RAS2 for guanine nucleotides apparently elevate the fraction of nucleotide-free RAS2, which has greater CDC25 affinity. Amino acid alterations that reduce the affinity of RAS2 for GTPase activating proteins included substitutions both within the switch I/switch II domain and distinctly outside it. One mutant, RAS2-Y78F, bound a lower fraction of GTP in vivo than the wild-type protein. The Y78F substitution is localized to the switch II domain, a region of the RAS protein that undergoes guanine nucleotide-dependent conformational changes.
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PMID:Novel, activated RAS mutations alter protein-protein interactions. 880 95

Ras proteins play the role of molecular switches by conformational change between a GTP and a GDP-bound state. In the yeast Saccharomyces cerevisiae, they are encoded by two partially redundant genes RAS1 and RAS2 with a different pattern of gene expression. They are essential for growth because they are required for the activation of the adenylate cyclase and thus the protein kinase A pathway. Other possible biological functions remains to be established. To achieve their biological function, they need to be processed after their synthesis, they are modified farnesylated and palmitoylated at their C-terminal end at their CaaX box. Palmitoylation, involved in membrane localization, is not essential for growth but required for glucose signaling whereas farnesylation appears to participate in adenylate cyclase activation. In the GTP-bound state ras proteins interact through their conserved effector domain with the adenylate cyclase, the product of the CYR1/CDC35 gene. They also interact with GTPase activating proteins encoded by IRA1 and IRA2. These proteins are specific for yeast ras. It has been shown that Ira2p recognizes specific residues of yeast ras not shared by mammalian ras. The interaction with the guanine nucleotide exchange factor (GEF) of the CDC25 family is enhanced by dominant negative mutations such as RAS2ala22. Using the two hybrid approach, we have showed the key role of position 80 in Ras2p and confirmed the involvement of the a2 helix, the other switching part of ras, in this interaction and the induced effect. As a counterpart we have identified positions in HGRF55 conserved in other GEF involved in ras interaction. The triggering elements of ras activation: the GEF Cdc25p and Sdc25p are limiting components of the ras system. Cdc25p is part of a multimolecular complex associated with the membrane. We have shown that it can form homodimers and heterodimers with Sdc25p. It is an unstable protein containing a cyclin destruction box. Therefore its activity on ras could be regulated by controlling its cellular content.
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PMID:[Ras proteins in Saccharomyces cerevisiae, their partners and their activation]. 925 49

In the yeast Saccharomyces cerevisiae the genes involved in galactose metabolism (GAL1,7,10) are transcriptionally activated more than a 1000-fold in the presence of galactose as the sole carbon source in the culture media. In the present work, we monitored the activity of the GAL10 gene promoter in different Ras-cAMP genetic backgrounds. We demonstrate that overexpression of C-terminus of the nucleotide exchange factor Cdc25p stimulates GAL10 transcription in yeast strains carrying the contemporary deletion of both RAS genes. Moreover, the deletion of the chromosomal CDC25 gene provokes impaired growth on galactose based media in yeast strain lacking both RAS genes and adenylate cyclase (whose viability is assured by the presence of the Bcy1-11 allele). Surprisingly, reconstitution of the Ras-pathway inhibits GAL10-promoter activation. Activation of GAL10 gene promoter is indeed possible in the presence of Ras protein but only in strains with chromosomal deletion of adenylate cyclase. These results indicate a dual role of Ras-pathway on galactose metabolism and suggest that Cdc25p has a Ras-independent role in cellular metabolism.
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PMID:Ras-pathway has a dual role in yeast galactose metabolism. 1747 60

Meiotic development (sporulation) in the yeast Saccharomyces cerevisiae is induced by nutritional deprivation. Smk1 is a meiosis-specific MAP kinase homolog that controls spore morphogenesis after the meiotic divisions have taken place. In this study, recessive mutants that suppress the sporulation defect of a smk1-2 temperature-sensitive hypomorph were isolated. The suppressors are partial function alleles of CDC25 and CYR1, which encode the Ras GDP/GTP exchange factor and adenyl cyclase, respectively, and MDS3, which encodes a kelch-domain protein previously implicated in Ras/cAMP signaling. Deletion of PMD1, which encodes a Mds3 paralog, also suppressed the smk1-2 phenotype, and a mds3-Delta pmd1-Delta double mutant was a more potent suppressor than either single mutant. The mds3-Delta, pmd1-Delta, and mds3-Delta pmd1-Delta mutants also exhibited mitotic Ras/cAMP phenotypes in the same rank order. The effect of Ras/cAMP pathway mutations on the smk1-2 phenotype required the presence of low levels of glucose. Ime2 is a meiosis-specific CDK-like kinase that is inhibited by low levels of glucose via its carboxy-terminal regulatory domain. IME2-DeltaC241, which removes the carboxy-terminal domain of Ime2, exacerbated the smk1-2 spore formation phenotype and prevented cyr1 mutations from suppressing smk1-2. Inhibition of Ime2 in meiotic cells shortly after Smk1 is expressed revealed that Ime2 promotes phosphorylation of Smk1's activation loop. These findings demonstrate that nutrients can negatively regulate Smk1 through the Ras/cAMP pathway and that Ime2 is a key activator of Smk1 signaling.
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PMID:The Ras/cAMP pathway and the CDK-like kinase Ime2 regulate the MAPK Smk1 and spore morphogenesis in Saccharomyces cerevisiae. 1908 57


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