AMPK phosphorylation by Ssp1 is required for proper sexual differentiation in fission yeast

Valbuena, Noelia; Moreno, Sergio

doi:10.1242/jcs.098533

Cited by 33 publications

(47 citation statements)

References 37 publications

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“…In wholecell extracts, we detected a specific band for wild-type cells grown in low (0.2%) glucose but not in high (3%) glucose (Fig. 1C), consistent with previous studies (21,26). This band was absent in ssp2Δ cells and migrated at the predicted higher molecular weight in lysates from cells expressing the fusion protein Ssp2-13-myc (Fig.…”

Section: Resultssupporting

confidence: 90%

“…Mutations in ssp1 ϩ lead to pleiotropic defects, including energy stress, cell cycle progression, and cell polarity (19)(20)(21)(22)(23), consistent with activation of fission yeast ARKs for diverse cellular functions. Genetic experiments place Ssp1 upstream of Ssp2/AMPK␣ for growth in low glucose (22,24,25), and Ssp1 is required for phosphorylation of Ssp2 under low-nitrogen or low-glucose conditions (21,26). Further, we recently identified Ssp1 as the sole upstream kinase for the activation loop of Cdr2 (27), an ARK that regulates cell size at division.…”

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confidence: 81%

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Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast

Deng

Lee

Schutt

et al. 2017

Molecular and Cellular Biology

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AMPK-related protein kinases (ARKs) coordinate cell growth, proliferation, and migration with environmental status. It is unclear how specific ARKs are activated at specific times. In the fission yeast Schizosaccharomyces pombe, the CaMKKlike protein kinase Ssp1 promotes cell cycle progression by activating the ARK Cdr2 according to cell growth signals. Here, we demonstrate that Ssp1 activates a second ARK, Ssp2/AMPK␣, for cell proliferation in low environmental glucose. Ssp1 activates these two related targets by the same biochemical mechanism: direct phosphorylation of a conserved residue in the activation loop (Cdr2-T166 and Ssp2-T189). Despite a shared upstream kinase and similar phosphorylation sites, Cdr2 and Ssp2 have distinct regulatory input cues and distinct functional outputs. We investigated this specificity and found that distinct protein phosphatases counteract Ssp1 activity toward its different substrates. We identified the PP6 family phosphatase Ppe1 as the primary phosphatase for Ssp2-T189 dephosphorylation. The phosphatase inhibitor Sds23 acts upstream of PP6 to regulate Ssp2-T189 phosphorylation in a manner that depends on energy but not on the intact AMPK heterotrimer. In contrast, Cdr2-T166 phosphorylation is regulated by protein phosphatase 2A but not by the Sds23-PP6 pathway. Thus, our study provides a phosphatase-driven mechanism to induce specific physiological responses downstream of a master protein kinase.KEYWORDS AMPK, Cdr2, Ssp1, fission yeast, kinase, phosphatase, pombe C ells control proliferation, polarized growth, and migration according to nutrient and environmental status. These processes must be tightly regulated during normal growth and development, and loss of this coordination is coupled with distinct steps in the initiation and maturation of tumors (1, 2). The AMP-activated protein kinase (AMPK)-related kinase (ARK) subfamily of protein kinases is essential for coordination of cell growth, proliferation, and migration with environmental status (3). Human cells express at least 13 members of this conserved kinase subfamily, including the metabolic sensor AMPK, the cytoskeletal kinase MARK1/Par-1, and the SAD kinases that regulate cell growth and polarity (4). Given their functions in diverse cell biological processes, it is remarkable that all ARKs can be activated by a shared upstream activating kinase, which phosphorylates the activation loop of ARK kinase domains to turn them "on" (4). To meet the needs of a rapidly changing environment, different ARKs need to be turned on and off at different times. This leads to a simple question: how does a common activation mechanism activate different ARKs at different times?The defining member of the ARK subfamily is AMPK. This conserved heterotrimeric complex is activated by low cellular energy status, typically the result of low levels of environmental nutrients (5). AMPK activation shifts cells toward catabolism and promotes the Warburg effect in cancer cells (5-7). The AMPK heterotrimer consists of a catalytic ␣ subun...

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Section: Resultssupporting

confidence: 90%

mentioning

confidence: 81%

Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast

Deng

Lee

Schutt

et al. 2017

Molecular and Cellular Biology

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“…Another pathway that has a positive effect on TORC2-Gad8 activity is the AMP-dependent pathway, composed of Ssp1-Ssp2 module (24,25). Deletion mutants in ssp1 ϩ or ssp2 ϩ resulted in down-regulation of Gad8 activity and Ser-546 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Ssp2 phosphorylates Scr1, a transcription repression factor involved in glucose-mediated transcription repression (24). Ssp2 is phosphorylated by Ssp1, a calmodulin-dependent kinase, and thereby recruited to the nucleus (25). These findings suggest a cross-talk between glucose-dependent signaling and the calcium/calmodulin pathway.…”

Section: Target Of Rapamycin (Tor)mentioning

confidence: 90%

“…A decrease in glucose is sensed by the AMP-dependent kinase Ssp2 (24), which was recently shown to be activated by the calmodulin-dependent kinase Ssp1 (25). To examine whether the AMP kinase pathway is involved in the regulation of Gad8 activity, we monitored Gad8 activity in mutants lacking ssp1 ϩ or ssp2 ϩ .…”

Section: Torc2-dependent Gad8 Phosphorylation and Gad8mentioning

confidence: 99%

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Glucose Activates TORC2-Gad8 Protein via Positive Regulation of the cAMP/cAMP-dependent Protein Kinase A (PKA) Pathway and Negative Regulation of the Pmk1 Protein-Mitogen-activated Protein Kinase Pathway

Cohen

Kupiec

Weisman

2014

Journal of Biological Chemistry

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Background: TORC2 is a conserved protein complex that regulates multiple aspects of cell survival and proliferation. Results: Gad8 is regulated by the cAMP-dependent protein kinase A and the Pmk1 protein-mitogen-activated protein kinase. Conclusion: Glucose is a major regulator of TORC2-Gad8 signaling. Significance: Identification of a novel mode of regulation of TORC2-Gad8 in response to glucose and stress.

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AMPK Activates Cellulase Secretion in Penicillium funiculosum by Downregulating P‐HOG1 MAPK Levels

Randhawa,

Sinha,

Das

et al. 2024

Journal of Basic Microbiology

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Cellulase production for hydrolyzing plant cell walls is energy‐intensive in filamentous fungi during nutrient scarcity. AMP‐activated protein kinase (AMPK), encoded by snf1, is known to be the nutrient and energy sensor in eukaryotes. Previous studies on AMPK identified its role in alternate carbon utilization in pathogenic fungi. However, the precise role of AMPK in cellulase production remains elusive. In the present study, we employed gene‐deletion analysis, quantitative proteomics and chemical‐genetic approaches to investigate the role of AMPK in cellulase synthesis in Penicillium funiculosum. Gene‐deletion analysis revealed that AMPK does not promote transcription and translation but is essential for cellulase secretion in a calcium‐dependent manner. Proteomic analysis of the snf1‐deleted (Δsnf1) strain confirmed trapped cellulase inside the mycelia and identified HOG1 MAPK activation as the most significant Ca2+‐induced signaling event during carbon stress in Δsnf1. Western blot analysis analysis revealed that the phosphorylated HOG1 (P‐HOG1)/HOG1 MAPK ratio maintained by Ca2+‐signaling/Ca2+‐activated AMPK, respectively, forms a secretion checkpoint for cellulases, and disturbing this equilibrium blocks cellulase secretion. The proteomic analysis also indicated a massive increase in mTORC1‐activated anabolic pathways during carbon stress in Δsnf1. Our study suggests that AMPK maintains homeostasis by acting as a global repressor during carbon stress.

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AMPK phosphorylation by Ssp1 is required for proper sexual differentiation in fission yeast

Cited by 33 publications

References 37 publications

Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast

Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast

Glucose Activates TORC2-Gad8 Protein via Positive Regulation of the cAMP/cAMP-dependent Protein Kinase A (PKA) Pathway and Negative Regulation of the Pmk1 Protein-Mitogen-activated Protein Kinase Pathway

AMPK Activates Cellulase Secretion in Penicillium funiculosum by Downregulating P‐HOG1 MAPK Levels

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