Turnover and bypass of p21-activated kinase during Cdc42-dependent MAPK signaling in yeast

González, Beatriz; Mirzaei, Mahnoosh; Basu, Sukanya; Pujari, Atindra N.; Vandermeulen, Matthew D.; Prabhakar, Aditi; Cullen, Paul J.

doi:10.1016/j.jbc.2023.105297

Cited by 3 publications

(3 citation statements)

References 133 publications

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“…2011 ). The proteasome is required for turnover of Cdc42p ( Gonzalez and Cullen 2022 ) and Ste20p ( Gonzalez et al . 2023 ), which are positive regulators of the fMAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Modulators of MAPK pathway activity during filamentous growth in Saccharomyces cerevisiae

Pujari,

Cullen

2024

G3: Genes, Genomes, Genetics

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Mitogen-activated protein kinase (MAPK) pathways control the response to intrinsic and extrinsic stimuli. In the budding yeast Saccharomyces cerevisiae, cells undergo filamentous growth, which is regulated by the fMAPK pathway. To better understand the regulation of the fMAPK pathway, a genetic screen was performed to identify spontaneous mutants with elevated activity of an fMAPK-pathway dependent growth reporter (ste4 FUS1-HIS3). In total, 159 mutants were isolated and analyzed by secondary screens for invasive growth by the plate-washing assay, and filament formation by microscopy. Thirty-two mutants were selected for whole-genome sequencing, which identified new alleles in genes encoding known regulators of the fMAPK pathway. These included gain-of-function alleles in STE11, which encodes the MAPKKK, as well as loss-of-function alleles in KSS1, which encodes the MAP kinase, and loss-of-function alleles in RGA1, which encodes a GTPase activating protein (GAP) for CDC42. New alleles in previously identified pathway modulators were also uncovered in ALY1, AIM44, RCK2, IRA2, REG1 and in genes that regulate protein folding (KAR2), glycosylation (MNN4), and turnover (BLM10). C-terminal truncations in the transcription factor Ste12p were also uncovered that resulted in elevated reporter activity, identifying an inhibitory domain of the protein from residues 491 to 688. We also find that a diversity of filamentous growth phenotypes can result from combinatorial effects of multiple mutations and by loss of different regulators of the response. The alleles identified here expand the connections surrounding MAPK pathway regulation and reveal new features of proteins that function in the signaling cascade.

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“…2011 ). The proteasome is required for turnover of Cdc42p ( Gonzalez and Cullen 2022 ) and Ste20p ( Gonzalez et al . 2023 ), which are positive regulators of the fMAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Modulators of MAPK pathway activity during filamentous growth in Saccharomyces cerevisiae

Pujari,

Cullen

2024

G3: Genes, Genomes, Genetics

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“…Bmh is a negative regulator of retrograde signaling; therefore, if mitochondria are dysfunctional and retrograde signaling is constitutively activated, mutations in BMH1 can be tolerated. Genetic approaches have also been used in another recent study on the MAPK signaling pathway, which controls fiber growth ( Gonzalez et al, 2023 ). This study proposed the existence of a Ste20p-independent branch (Ste20p is a yeast p21-activated kinase) of this pathway involving adaptor protein Bem4p, whereas the Ste20p-dependent branch requires Bmh1/2 proteins.…”

Section: 14-3-3 Proteins Regulate Fundamental Cellular Processes In Y...mentioning

confidence: 99%

The yeast 14-3-3 proteins Bmh1 and Bmh2 regulate key signaling pathways

Obsilova,

Obsil

2024

Front. Mol. Biosci.

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Cell signaling regulates several physiological processes by receiving, processing, and transmitting signals between the extracellular and intracellular environments. In signal transduction, phosphorylation is a crucial effector as the most common posttranslational modification. Selectively recognizing specific phosphorylated motifs of target proteins and modulating their functions through binding interactions, the yeast 14-3-3 proteins Bmh1 and Bmh2 are involved in catabolite repression, carbon metabolism, endocytosis, and mitochondrial retrograde signaling, among other key cellular processes. These conserved scaffolding molecules also mediate crosstalk between ubiquitination and phosphorylation, the spatiotemporal control of meiosis, and the activity of ion transporters Trk1 and Nha1. In humans, deregulation of analogous processes triggers the development of serious diseases, such as diabetes, cancer, viral infections, microbial conditions and neuronal and age-related diseases. Accordingly, the aim of this review article is to provide a brief overview of the latest findings on the functions of yeast 14-3-3 proteins, focusing on their role in modulating the aforementioned processes.

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“…The proteasome is required for turnover of Cdc42p (GONZALEZ AND CULLEN 2022) and Ste20p (GONZALEZ et al 2023), which are positive regulators of the fMAPK pathway. Therefore, cells lacking the ability to degrade these proteins might show elevated activity of the fMAPK pathway.…”

Section: Other Genesmentioning

confidence: 99%

Modulators of MAPK pathway activity during filamentous growth inSaccharomyces cerevisiae

Pujari,

Cullen

2023

Preprint

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Mitogen-activated protein kinase (MAPK) pathways control the response to intrinsic and extrinsic stimuli. In the budding yeastSaccharomyces cerevisiae, cells undergo filamentous growth, which is regulated by the fMAPK pathway. To better understand the regulation of the fMAPK pathway, a genetic screen was performed to identify spontaneous mutants with elevated activity of an fMAPK-pathway dependent growth reporter (ste4 FUS1-HIS3). In total, 159 mutants were isolated and analyzed by secondary screens for invasive growth by the plate-washing assay, and filament formation by microscopy. Thirty-two mutants were selected for whole-genome sequencing, which identified new alleles in genes encoding known regulators of the fMAPK pathway. These included gain-of-function alleles inSTE11,which encodes the MAPKKK, as well as loss-of-function alleles inKSS1,which encodes the MAP kinase, andRGA1,which encodes a GTPase activating protein (GAP) forCDC42. New alleles in previously identified pathway modulators were also uncovered inALY1, AIM44, RCK2, IRA2, REG1and in genes that regulate protein folding (KAR2), glycosylation (MNN4), and turnover (BLM10). C-terminal truncations in the transcription factor Ste12p were also uncovered that resulted in elevated reporter activity, presumably identifying an inhibitory domain in the C-terminus of the protein. We also show that a wide variety of filamentous growth phenotypes result from mutations in different regulators of the response. The alleles identified here expand the connections surrounding MAPK pathway regulation and reveal new features of proteins that function in the signaling cascade.ARTICLE SUMMARYSignaling pathways control the response to stimuli. In yeast, a signaling (MAPK) pathway controls a fungal behavioral response called filamentous growth. A genetic screen was performed to identify spontaneous mutants that show hyperactivity of a MAPK pathway-dependent reporter. Select mutants were analyzed by whole-genome sequencing. New alleles in known regulatory proteins were identified. A potential inhibitory domain in the C-terminus of the transcription factor Ste12p was also uncovered. Our results indicate that filamentous growth is determined by the combinatorial effects of multiple positive and negative regulatory inputs.

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Turnover and bypass of p21-activated kinase during Cdc42-dependent MAPK signaling in yeast

Cited by 3 publications

References 133 publications

Modulators of MAPK pathway activity during filamentous growth in Saccharomyces cerevisiae

Modulators of MAPK pathway activity during filamentous growth in Saccharomyces cerevisiae

The yeast 14-3-3 proteins Bmh1 and Bmh2 regulate key signaling pathways

Modulators of MAPK pathway activity during filamentous growth inSaccharomyces cerevisiae

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