Calcineurin, the Ca2+-dependent phosphatase, regulates Rga2, a Cdc42 GTPase-activating protein, to modulate pheromone signaling
Open accessAbstract
Calcineurin, the conserved Ca 2+/calmodulin-activated phosphatase, is required for viability during prolonged exposure to pheromone and acts through multiple substrates to down-regulate yeast pheromone signaling. Calcineurin regulates Dig2 and Rod1/Art4 to inhibit mating-induced gene expression and activate receptor internalization, respectively. Recent systematic approaches identified Rga2, a GTPase-activating protein (GAP) for the Cdc42 Rho-type GTPase, as a calcineurin substrate. Here we establish a physiological context for this regulation and show that calcineurin dephosphorylates and positively regulates Rga2 during pheromone signaling. Mating factor activates the Fus3/MAPK kinase, whose substrates induce gene expression, cell cycle arrest, and formation of the mating projection. Our studies demonstrate that Fus3 also phosphorylates Rga2 at inhibitory S/TP sites, which are targeted by Cdks during the cell cycle, and that calcineurin opposes Fus3 to activate Rga2 and decrease Cdc42 signaling. Yeast expressing an Rga2 mutant that is defective for regulation by calcineurin display increased gene expression in response to pheromone. This work is the first to identify cross-talk between Ca 2+/calcineurin and Cdc42 signaling and to demonstrate modulation of Cdc42 activity through a GAP during mating.
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Apart from RCN1, only two genes on this list (BOI2, RGA2) encode homologs that were found to be dephosphorylated by calcineurin in S. cerevisiae.
“Apart from RCN1, only two genes on this list (BOI2, RGA2; both involved in polarized cell growth) encode homologs that were found to be dephosphorylated by calcineurin in S. cerevisiae (62, 63).”
From Echinocandin tolerance and persistence <i>in vitro</i> are regulated by calcineurin signaling in <i>Candida glabrata</i> (2026) · cites this paper as [63]
The Results and Discussion section (page unavailable) states that Rga2 is dephosphorylated by calcineurin in S. cerevisiae. Our copy does not establish the corresponding claim for BOI2 or the assertion that these are the only two genes on the citing document’s list. (LLM, conf=0.88)
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“Apart from RCN1 , only two genes on this list ( BOI2 , RGA2 ; both involved in polarized cell growth) encode homologs that were found to be dephosphorylated by calcineurin in S. cerevisiae (62, 63).”
MODELING POLARITY SITE MOVEMENT IN YEAST VIA CALCIUM-MEDIATED REGULATION OF GAP ACTIVITYPreprint
Parikh, V. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.20.521256
- Authors
- Ly, N., & Cyert, M. S.
- Affiliations
- Duke University (US)
- Corresponding author
- Cyert, Martha S.
- ORCID
- Cyert, Martha S.
- Venue
- Molecular Biology of the Cell
- Published
- 2017-03
- Volume
- 28
- Issue
- 5
- Pages
- 576-586
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC5328617
- OpenAlex
- W2579208377
- Cited by
- 14
- References
- 65
- Citations by year
- 2025: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 3 · 2016: 1
- FWCI
- 0.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM008412, T32GM007276, R01GM048729)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- calcineurin, Cdc42, GTPase-activating protein, pheromone signaling, mating, FUS3, MAPK signaling, dephosphorylation, Ca2+/calmodulin signaling, Cdc42 signaling, Saccharomyces cerevisiae, mating projections
- MeSH terms
- Cell Cycle, Pheromones, Phosphorylation, Saccharomyces cerevisiae, Signal Transduction, GTP-Binding Protein alpha Subunits, Gi-Go, Calcineurin, GTP Phosphohydrolases, GTPase-Activating Proteins, cdc42 GTP-Binding Protein, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Saccharomyces cerevisiae Proteins
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