The metabolic sensor PASK is a histone 3 kinase that also regulates H3K4 methylation by associating with H3K4 MLL2 methyltransferase complex

Karakkat, Jimsheena V; Kaimala, Suneesh; Sreedharan, Sreejisha P; Jayaprakash, Princy; Adeghate, Ernest; Ansari, Suraiya A.; Guccione, Ernesto; Mensah-Brown, Eric; Emerald, Bright Starling

doi:10.1093/nar/gkz786

Cited by 16 publications

(15 citation statements)

References 76 publications

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“…VRK3 is unlikely to contribute as it is a pseudokinase with a degraded active site structure (31) that is unable to bind divalent cations or ATP (54), and is unable to phosphorylate casein or H3 (20,55). In addition, PASK did not score highly as a mitotic H3T3 kinase in either KiPIK or RNAi screens, concordant with the finding that CRISPR/Cas9 targeting of the PASK gene did not markedly alter H3T3ph in mouse C2C12 cells (53).…”

Section: Discussionsupporting

confidence: 71%

“…These results are consistent with previous KiPIK screens for H3T3 kinases (48), where Haspin was the top overall hit, but VRK1 and VRK2 were never within the top 30% and were most often in the bottom 20% of kinases (Figure 2F; Figure S1). Of note, another kinase that has been proposed to phosphorylate a number of sites on H3 including H3T3, PASK (53), was also not a notable hit in these screens (Figure 2, Figure S1). Therefore, Haspin was reproducibly identified as the most likely mitotic H3T3 kinase in HeLa cell extracts.…”

Section: A Kinase Activity Screen Implicates Haspin Not Vrks As the Mitotic H3t3 Kinasementioning

confidence: 98%

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Dissecting the roles of Haspin and VRK1 in Histone H3 threonine-3 phosphorylation during mitosis

Cartwright

Harris

Meyer

et al. 2021

Preprint

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Protein kinases that phosphorylate histones are ideally-placed to influence the behavior of chromosomes during cell division. Indeed, a number of conserved histone phosphorylation events occur prominently during mitosis and meiosis in most eukaryotes, including on histone H3 at threonine-3 (H3T3ph). At least two kinases, Haspin and VRK1 (NHK-1/ballchen in Drosophila), have been proposed to carry out this modification. Phosphorylation of H3 by Haspin has defined roles in mitosis, but the significance of VRK1 activity towards histones in dividing cells has been unclear. Here, using in vitro kinase assays, KiPIK screening, RNA interference, and CRISPR/Cas9 approaches, we were unable to substantiate a direct role for VRK1, or its homologue VRK2, in the phosphorylation of threonine-3 or serine-10 of Histone H3 in mitosis, although loss of VRK1 did slow cell proliferation. We conclude that the role of VRK1, and its more recently identified association with neuromuscular disease in humans, is unlikely to involve mitotic histone kinase activity. In contrast, Haspin is required to generate H3T3ph during mitosis.

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Section: Discussionsupporting

confidence: 71%

Section: A Kinase Activity Screen Implicates Haspin Not Vrks As the Mitotic H3t3 Kinasementioning

confidence: 98%

Dissecting the roles of Haspin and VRK1 in Histone H3 threonine-3 phosphorylation during mitosis

Cartwright

Harris

Meyer

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, it has been confirmed that the metabolic sensor PASK could affect both the phosphorylation and the methylation of histone H3 tails. It contributes to the methylation of H3 lysine 4 (H3K4) di-and tri-methylation through its association with the H3K4 MLL2 methyltransferase complex and to the phosphorylation of several threonine residues (T3, T6 and T11) and serine (S10) on H3 as a histone kinase [101]. The methylation of histone H3 lysine 4 H3K4 has been linked to transcriptional activation.…”

Section: Pask: a New Nutrient Sensormentioning

confidence: 99%

Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

Hurtado-Carneiro¹,

Pérez-García²,

Álvarez³

et al. 2021

Type 2 Diabetes - From Pathophysiology to Cyber Systems

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Cell survival depends on the constant challenge to match energy demands with nutrient availability. This process is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both a cellular and whole-body energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor in the development of type 2 diabetes, obesity, metabolic syndrome, and other associated pathologies; thus, understanding the fundamental mechanisms by which cells detect nutrient availability and energy demand may lead to the development of new treatments. This chapter reviews the role of the sensor PASK (protein kinase with PAS domain), analyzing its role in the mechanisms of adaptation to nutrient availability and the metabolic response in different organs (liver, hypothalamus) actively cooperating to control food intake, maintain glycaemia homeostasis, and prevent insulin resistance and weight gain.

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“…PASK phosphorylates Wdr5, activating the trimethylation of the lysine 4 of histone H3 (H3K4me3) and the subsequent expression of myogenin, prompting muscle differentiation (55) ( Figure 1A). PASK has been found to associate with the mammalian H3K4 MLL2 methyltransferase complex (56). PASK's ability to regulate epigenetic modifications may explain how this protein kinase regulates the expression of a large number of genes.…”

Section: Pask Epigenetics and Differentiationmentioning

confidence: 99%

PAS Kinase: A Nutrient and Energy Sensor “Master Key” in the Response to Fasting/Feeding Conditions

Hurtado-Carneiro¹,

Pérez-García²,

Álvarez³

et al. 2020

Front. Endocrinol.

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The protein kinase with PAS domains (PASK) is a nutrient and energy sensor located in the cells of multiple organs. Many of the recent findings for understanding PASK functions in mammals have been reported in studies involving PASK-deficient mice. This minireview summarizes the PASK role in the control of fasting and feeding responses, focusing especially on the hypothalamus and liver. In 2013, PASK was identified in the hypothalamic areas involved in feeding behavior, and its expression was regulated under fasting/refeeding conditions. Furthermore, it plays a role in coordinating the activation/inactivation of the hypothalamic energy sensors AMPK and mTOR/S6K1 pathways in response to fasting. On the other hand, PASK deficiency prevents the development of obesity and non-alcoholic fatty liver in mice fed with a high-fat diet. This protection is explained by the re-establishment of several high-fat diet metabolic alterations produced in the expression of hepatic transcription factors and key enzymes that control the main metabolic pathways involved in maintaining metabolic homeostasis in fasting/feeding responses. This minireview covers the effects of PASK inactivation in the expression of certain transcription factors and target enzymes in several metabolic pathways under situations such as fasting and feeding with either a standard or a high-fat diet.

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The metabolic sensor PASK is a histone 3 kinase that also regulates H3K4 methylation by associating with H3K4 MLL2 methyltransferase complex

Cited by 16 publications

References 76 publications

Dissecting the roles of Haspin and VRK1 in Histone H3 threonine-3 phosphorylation during mitosis

Dissecting the roles of Haspin and VRK1 in Histone H3 threonine-3 phosphorylation during mitosis

Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

PAS Kinase: A Nutrient and Energy Sensor “Master Key” in the Response to Fasting/Feeding Conditions

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