Ubiquitination is a post-translational modification that tags proteins for proteasomal degradation. In addition, there is a growing appreciation that ubiquitination can influence protein activity and localization. Ste7 is a prototype MAPKK in yeast that participates in both the pheromone signaling and nutrient deprivation/invasive growth pathways. We have shown previously that Ste7 is ubiquitinated upon pheromone stimulation. Here, we show that the Skp1/Cullin/F-box ubiquitin ligase SCF(Cdc4) and the ubiquitin protease Ubp3 regulate Ste7 ubiquitination and signal specificity. Using purified components, we demonstrate that SCF(Cdc4) ubiquitinates Ste7 directly. Using gene deletion mutants, we show that SCF(Cdc4) and Ubp3 have opposing effects on Ste7 ubiquitination. Although SCF(Cdc4) is necessary for proper activation of the pheromone MAPK Fus3, Ubp3 is needed to limit activation of the invasive growth MAPK Kss1. Finally, we show that Fus3 phosphorylates Ubp3 directly and that phosphorylation of Ubp3 is necessary to limit Kss1 activation. These results reveal a feedback loop wherein one MAPK limits the ubiquitination of an upstream MAPKK and thereby prevents spurious activation of a second competing MAPK.
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| Gene | Phenotype | Experiment Type | Mutant Information | Strain Background | Chemical | Details |
|---|---|---|---|---|---|---|
| CDC4 | protein/peptide modification: decreased Reporter: Fus3p | classical genetics | repressible | S288C | ||
| UBP3 | protein/peptide modification: increased Reporter: Ste7p | classical genetics | null Allele: ubp3-Δ | S288C |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Interactor | Interactor | Assay | Annotation | Action | Modification | |
|---|---|---|---|---|---|---|
Figure 1 | CDC4 | STE7 | Affinity Capture-Western | manually curated | Bait-Hit | No Modification |
E1: Uba1|E2: Cdc34|Figure 1 | CDC4 | STE7 | Biochemical Activity | manually curated | Bait-Hit | ubiquitinylated lysine |
Figure 1 | CDC4 | CDC34 | Reconstituted Complex | manually curated | Bait-Hit | No Modification |
Figure 6 | FUS3 | UBP3 | Biochemical Activity | manually curated | Bait-Hit | phosphorylated residue |