The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway

Broek, Daniel; Toda, Takashi; Michaeli, Tamar; Levin, Lonny R.; Birchmeier, Carmen; Zoller, Mark J.; Powers, Scott; Wigler, Michael

doi:10.1016/0092-8674(87)90076-6

Cited by 489 publications

(328 citation statements)

References 34 publications

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“…3 GEFs activate Ras proteins through one or more catalytic domains homologous with the minimal Ras activation domain from CDC25, yeast GEF that activates Saccharomyces cerevisiae Ras. 19 The crystallographic structure of the interaction of the CDC25 domain of Sos1 and H-Ras has revealed the details of this interaction. 7 GEFs exhibit a large range of additional structural features that enable them to respond to many different signals.…”

Section: Discussionmentioning

confidence: 99%

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

et al. 2010

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Guanine-nucleotide exchange factors (GEFs) stimulate the intrinsic GDP/GTP exchange activity of Ras and promote the formation of active Ras-GTP, which in turn controls diverse signalling networks important for the regulation of cell proliferation, survival, differentiation, vesicular trafficking, and gene expression. RasGEF1b is a GEF, whose expression is induced in macrophages on stimulation with toll-like receptor (TLR) agonists. Here, we showed that in vitro RasGEF1b expression by macrophages is mostly induced by TLR3 (poly I:C) and TLR4 (lipopolysaccharyde) through the MyD88-independent pathway. In vivo infection with the protozoan parasites Trypanosoma cruzi and Plasmodium chabaudi induced RasGEF1b in an MyD88-, TRIF-, and IFN-g-dependent manner. Ectopically expressed RasGEF1b was found, mostly, in the heavy membrane fraction of HEK 293T, and by confocal microscopy, it was found to be located at early endosomes. Computational modelling of the RasGEF1b-Ras interaction revealed that RasGEF1b interacts with the binding domain site of Ras, a critical region for interacting with GEFs involved in the activation of Ras-Raf-MEK-ERK pathway. More important, RasGEF1b was found to be closely associated with Ras in live cells and to trigger Ras activity. Altogether, these results indicate that on TLR activation, RasGEF1b may trigger Ras-like proteins and regulate specific biological activities described for this subtype of GTPases.

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Section: Discussionmentioning

confidence: 99%

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

et al. 2010

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“…On the other hand the data obtained on temperaturesensitive mutants suggest that the CDC25 gene product that is postulated to be a mediator of glucose response for adenylate cyclase activation [2,3,7], is not involved in glucose-mediated PI stimulation, and also that the stimulus appears to be RAS-independent, as indicated by the data observed with rasl, ras2-ts strain. The two cdc25 alleles used show a difference for cAMP metabolism at restrictive temperature.…”

Section: Cdc25 Ras1mentioning

confidence: 93%

“…In fact mutations that decrease the intracellular cAMP level bring about both a cell cycle arrest in the G0/G1 phase and a growth arrest, while mutant strains that show high unregulated cAMP levels fail to arrest the cell cycle during starvation conditions [1]. The cAMP level appears to be regulated throughout a signal transduction pathway, that operates in response to nutrients availability and involves the activity of the CDC25, RAS1 and RAS2 gene products [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Since the CDC25 gene product operates upstream to the RAS proteins [2,3], we studied the PI turnover in cdc25-1 and cdc25-5 mutants, and we report in this note that, under our experimental conditions, the glucoseinduced stimulation of PI turnover does not appear to be dependent upon the CDC25 activity and that also it is not related to the G0/G 1 arrest, but it seems to directly respond to glucose addition independently from the position of the cell cycle arrest. Moreover it does not appear to be related to the transient increase of intracellular cAMP.…”

Section: Introductionmentioning

confidence: 99%

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The glucose‐induced polyphosphoinositides turnover in Saccharomyces cerevisiae is not dependent on the CDC25‐RAS mediated signal transduction pathway

1990

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Recently the polyphosphoinositides (PI) turnover has been related to the control of growth and cell cycle also in Saccharomyces cerevisiae, and the RAS2 and RASI gene products have been shown to be involved in the stimulation of PI turnover in G0/G 1 arrested yeast cells. Here we show that addition of glucose to previously glucose-starved cells, stimulates the PI turnover with fast kinetics also in yeast cells that were not arrested in the G0/G 1 phase of the cell cycle. In addition PI turnover is equally stimulated in temperature sensitive cdc25-1 and cdc25-5 strains at restrictive temperature, as well as in rasl,ras2-ts strain, suggesting that PI turnover stimulation is not dependent on the CDC25-RAS mediated signal transduction pathway.

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“…An additional homological protein named RalGPS2 was identified from mouse (Rebhun et al, 2000). RalGPS contains a 30 kDa N-terminal catalytic domain (known as the Cdc25 domain), which shares about 30% sequence identity with the equivalent domain of other Ras GEFs and the Saccharomyces cerevisiae Cdc25 (Broek et al, 1987). A proline rich region (about 15 residues in length), termed the PXXP motif, exists in the central part of the full length peptide sequence.…”

Section: Introductionmentioning

confidence: 99%

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Peng

Guan

et al. 2011

Protein Cell

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The guanine-nucleotide exchange factor (GEF) RalGPS1a activates small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thus regulating various downstream cellular processes. RalGPS1a is composed of an Nterminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal pleckstrin homology (PH) domain. The Cdc25 domain of RalGPS1a, which shares about 30% sequence identity with other Cdc25-domain proteins, is thought to be directly engaged in binding and activating the substrate Ral protein. Here we report the crystal structure of the Cdc25 domain of RalGPS1a. The bowl shaped structure is homologous to the Cdc25 domains of SOS and RasGRF1. The most remarkable difference between these three Cdc25 domains lies in their active sites, referred to as the helical hairpin region. Consistent with previous enzymological studies, the helical hairpin of RalGPS1a adopts a conformation favorable for substrate binding. A modeled RalGPS1a-RalA complex structure reveals an extensive binding surface similar to that of the SOS-Ras complex. However, analysis of the electrostatic surface potential suggests an interaction mode between the RalGPS1a active site helical hairpin and the switch 1 region of substrate RalA distinct from that of the SOS-Ras complex.

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The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway

Cited by 489 publications

References 34 publications

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor

The glucose‐induced polyphosphoinositides turnover in Saccharomyces cerevisiae is not dependent on the CDC25‐RAS mediated signal transduction pathway

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

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