Ptc1 Protein Phosphatase 2C Contributes to Glucose Regulation of SNF1/AMP-activated Protein Kinase (AMPK) in Saccharomyces cerevisiae

Ruiz, Amparo; Xu, Xinjing; Carlson, Marian

doi:10.1074/jbc.m113.503763

Cited by 37 publications

(31 citation statements)

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“…However, inappropriately elevated Snf1 activity may be deleterious to cell growth (13,44). Consistent with this idea, the reg1⌬ ubp8⌬ ubp10⌬ mutant may sense elevated Snf1 activity and then transmit a signal to a Snf1 synthesis mediator to restore Snf1 protein levels (Figs.…”

Section: Discussionsupporting

confidence: 59%

“…3G). To test the hypothesis that Snf1 protein level can also be altered in response to its phosphorylation status, we deleted REG1 to impair Snf1 dephosphorylation (12,13,43,44). Surprisingly, although deletion of REG1 (encoding a dominant phosphatase of Snf1) did not affect Snf1 phosphorylation in ubp8⌬ ubp10⌬ cells (Fig.…”

Section: Enhanced Phosphorylation Of Snf1 Restores Its Protein Level mentioning

confidence: 99%

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Feedback Control of Snf1 Protein and Its Phosphorylation Is Necessary for Adaptation to Environmental Stress

Hsu

Liu

Yeh

et al. 2015

Journal of Biological Chemistry

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Background: Snf1/AMPK activity plays a vital role in adaptation to environmental stress. Results: Elevation of Snf1 phosphorylation restores Snf1 protein in a mutant with low Snf1 levels. Conclusion: Snf1 activity is fine-tuned by a dynamic feedback loop between its protein level and phosphorylation status. Significance: Our results reveal a previously unknown regulatory mechanism of Snf1 activity that is crucial for stress response and aging.

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Section: Discussionsupporting

confidence: 59%

Section: Enhanced Phosphorylation Of Snf1 Restores Its Protein Level mentioning

confidence: 99%

Feedback Control of Snf1 Protein and Its Phosphorylation Is Necessary for Adaptation to Environmental Stress

Hsu

Liu

Yeh

et al. 2015

Journal of Biological Chemistry

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“…Subsequent work demonstrated that Ptc1 is required for normal TOR signaling by regulating, in a HOG-independent manner, a step upstream of the Sit4 phosphatase (Gonzalez et al 2009). Recently, Ptc1 has been shown to dephosphorylate the Snf1 protein kinase at Thr 210 in vivo (Ruiz et al 2013).Early work showed that mutations in PTC1 could suppress phenotypes derived from hypoactive pkc1 alleles (Huang and Symington 1995), thus pointing to a link between Ptc1 and the cell-wall integrity (CWI) pathway. This pathway is composed of several membrane sensors that signal through the small GTPase Rho1 to the Pkc1 kinase.…”

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confidence: 99%

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confidence: 99%

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

et al. 2015

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The Saccharomyces cerevisiae type 2C protein phosphatase Ptc1 is required for a wide variety of cellular functions, although only a few cellular targets have been identified. A genetic screen in search of mutations in protein kinase-encoding genes able to suppress multiple phenotypic traits caused by the ptc1 deletion yielded a single gene, MKK1, coding for a MAPK kinase (MAPKK) known to activate the cell-wall integrity (CWI) Slt2 MAPK. In contrast, mutation of the MKK1 paralog, MKK2, had a less significant effect. Deletion of MKK1 abolished the increased phosphorylation of Slt2 induced by the absence of Ptc1 both under basal and CWI pathway stimulatory conditions. We demonstrate that Ptc1 acts at the level of the MAPKKs of the CWI pathway, but only the Mkk1 kinase activity is essential for ptc1 mutants to display high Slt2 activation. We also show that Ptc1 is able to dephosphorylate Mkk1 in vitro. Our results reveal the preeminent role of Mkk1 in signaling through the CWI pathway and strongly suggest that hyperactivation of Slt2 caused by upregulation of Mkk1 is at the basis of most of the phenotypic defects associated with lack of Ptc1 function.KEYWORDS synthetic genetic interactions; cell-wall integrity pathway; protein dephosphorylation; Saccharomyces cerevisiae P ROTEIN kinases play an essential role in nearly every aspect of cell physiology, and the activity of these key players is frequently modulated by phosphorylation. Therefore, protein phosphatases (PPases) are important regulators of protein kinases and cellular homeostasis. Among them, type 2C Ser/Thr PPases constitute an evolutionarily conserved group that, in contrast to other PPase families, are monomeric enzymes apparently lacking regulatory subunits. In the yeast Saccharomyces cerevisiae, seven members (Ptc1-Ptc7) have been identified and at least partially characterized [see Arino et al. (2011) for a review].Ptc1 is the closest homolog of human Wip1, a phosphatase involved in the regulation of stress-induced and DNA damage-induced networks in diverse physiologic and pathologic conditions (Le Guezennec and Bulavin 2010;Zhu and Bulavin 2012) and by far the most widely studied yeast isoform. Both the large number of characteristic phenotypes and the specific changes in the transcriptomic profile (Gonzalez et al. 2006) derived from deletion of the gene suggest that this phosphatase is involved in a large variety of cellular processes not shared by other Ptc family members. Early evidence indicated that Ptc1 was involved in the negative regulation of the high-osmolarity glycerol (HOG) pathway (Maeda et al. 1993;Maeda et al. 1994), and subsequent work demonstrated that Ptc1 could dephosphorylate the Hog1 MAPK in vitro and in vivo (Warmka et al. 2001 interacts with the N-terminal domain of Nbp2, an SH3 domaincontaining protein that serves as an adaptor for the recruitment of Ptc1 to the Pbs2-Hog1 complex, and this interaction is necessary for Ptc1 to participate in the regulation of HOGmediated signaling (Uetz et al. 2000;Ito et al. 2001;Ma...

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“…Budding yeast AMPK activation highlights the importance of phosphatases, as the upstream activating kinases do not appear to be regulated (8,16). Rather, dynamic control may come from protein phosphatases, and PP2C, PP1, and PP6 have been implicated in deactivating budding yeast AMPK (10,17,18).…”

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confidence: 99%

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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Ptc1 Protein Phosphatase 2C Contributes to Glucose Regulation of SNF1/AMP-activated Protein Kinase (AMPK) in Saccharomyces cerevisiae

Cited by 37 publications

References 38 publications

Feedback Control of Snf1 Protein and Its Phosphorylation Is Necessary for Adaptation to Environmental Stress

Feedback Control of Snf1 Protein and Its Phosphorylation Is Necessary for Adaptation to Environmental Stress

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast

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