Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation

Humphrey, Sean J.; James, David E.; Mann, Matthias

doi:10.1016/j.tem.2015.09.013

Cited by 451 publications

(344 citation statements)

References 115 publications

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“…Recently, we demonstrate that substitution of the N‐terminal lysine residues of the endogenous, but fused hexose transporters Hxt36 resulted in improved membrane localization and cell growth on xylose up to the late stage of sugar fermentation (Nijland et al, 2016). Ubiquitylation plays a prominent role in hexose transporters degradation (Horak and Wolf, 1997; Nijland et al, 2016; Roy et al, 2014), whereas phosphorylation is the primary mechanism for regulating cellular signaling (Humphrey et al, 2015). However, distinct phosphorylation sites are often used in conjunction with ubiquitylation in degradation, and these distinct sites are more highly conserved than the entire set of phosphorylation sites (Swaney et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

The amino‐terminal tail of Hxt11 confers membrane stability to the Hxt2 sugar transporter and improves xylose fermentation in the presence of acetic acid

Shin

Nijland

Waal

et al. 2017

Biotech & Bioengineering

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Hxt2 is a glucose repressed, high affinity glucose transporter of the yeast Saccharomyces cerevisiae and is subjected to high glucose induced degradation. Hxt11 is a sugar transporter that is stably expressed at the membrane irrespective the sugar concentration. To transfer this property to Hxt2, the N‐terminal tail of Hxt2 was replaced by the corresponding region of Hxt11 yielding a chimeric Hxt11/2 transporter. This resulted in the stable expression of Hxt2 at the membrane and improved the growth on 8% d‐glucose and 4% d‐xylose. Mutation of N361 of Hxt11/2 into threonine reversed the specificity for d‐xylose over d‐glucose with high d‐xylose transport rates. This mutant supported efficient sugar fermentation of both d‐glucose and d‐xylose at industrially relevant sugar concentrations even in the presence of the inhibitor acetic acid which is normally present in lignocellulosic hydrolysates. Biotechnol. Bioeng. 2017;114: 1937–1945. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

The amino‐terminal tail of Hxt11 confers membrane stability to the Hxt2 sugar transporter and improves xylose fermentation in the presence of acetic acid

Shin

Nijland

Waal

et al. 2017

Biotech & Bioengineering

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“…Our study here suggests that the phosphorylation of sPPases also can be modulated by lowered [pH] cyt and identifies several amino acids as being involved in the modulation of PPase activity by amplifying pH sensitivity. Many cellular processes are regulated by reversible protein phosphorylation, and identifying the targets, sites, and protein kinases involved is crucial to understand how these important posttranslational modifications affect biological function (Humphrey et al, 2015). Although many target kinases are known to be phosphorylated, few nonsignaling proteins have been highlighted (Mayank et al, 2012).…”

Section: What Is the Biological Significance Of Sppase Phosphorylation?mentioning

confidence: 99%

“…Numerous cellular processes are regulated by reversible protein phosphorylation (Humphrey et al, 2015), including metabolism, cell cycle progression, differentiation, biotic and abiotic stress tolerance, and apoptosis. Many metabolic enzymes are regulated by phosphorylation.…”

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confidence: 99%

Identification of Phosphorylation Sites Altering Pollen Soluble Inorganic Pyrophosphatase Activity

et al. 2017

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Protein phosphorylation regulates numerous cellular processes. Identifying the substrates and protein kinases involved is vital to understand how these important posttranslational modifications modulate biological function in eukaryotic cells. Pyrophosphatases catalyze the hydrolysis of inorganic phosphate (PP i ) to inorganic phosphate P i , driving biosynthetic reactions; they are essential for low cytosolic inorganic phosphate. It was suggested recently that posttranslational regulation of Family I soluble inorganic pyrophosphatases (sPPases) may affect their activity. We previously demonstrated that two pollenexpressed sPPases, Pr-p26.1a and Pr-p26.1b, from the flowering plant Papaver rhoeas were inhibited by phosphorylation. Despite the potential significance, there is a paucity of data on sPPase phosphorylation and regulation. Here, we used liquid chromatographic tandem mass spectrometry to map phosphorylation sites to the otherwise divergent amino-terminal extensions on these pollen sPPases. Despite the absence of reports in the literature on mapping phosphorylation sites on sPPases, a database survey of various proteomes identified a number of examples, suggesting that phosphorylation may be a more widely used mechanism to regulate these enzymes. Phosphomimetic mutants of Pr-p26.1a/b significantly and differentially reduced PPase activities by up to 2.5-fold at pH 6.8 and 52% in the presence of Ca 2+ and hydrogen peroxide over unmodified proteins. This indicates that phosphoregulation of key sites can inhibit the catalytic responsiveness of these proteins in concert with key intracellular events. As sPPases are essential for many metabolic pathways in eukaryotic cells, our findings identify the phosphorylation of sPPases as a potential master regulatory mechanism that could be used to attenuate metabolism.

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“…This introduces the potential for huge combinatorial signalling complexity. Finally, cellular studies are beginning to unpick the importance of different temporal sequences of signalling events after receptor stimulation, which, allied to different thresholds for activation of metabolic endpoints, introduces yet more tiers of signalling complexity (15).…”

Section: Mechanisms Of Insulin Actionmentioning

confidence: 99%

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

Semple¹

2016

European Journal of Endocrinology

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Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, 'insulin resistance (IR)', a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.

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Protein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation

Cited by 451 publications

References 115 publications

The amino‐terminal tail of Hxt11 confers membrane stability to the Hxt2 sugar transporter and improves xylose fermentation in the presence of acetic acid

The amino‐terminal tail of Hxt11 confers membrane stability to the Hxt2 sugar transporter and improves xylose fermentation in the presence of acetic acid

Identification of Phosphorylation Sites Altering Pollen Soluble Inorganic Pyrophosphatase Activity

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

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