Human Mutation within Per-Arnt-Sim (PAS) Domain-containing Protein Kinase (PASK) Causes Basal Insulin Hypersecretion

Semplici, Francesca; Vaxillaire, Martine; Fogarty, Sarah; Semache, Meriem; Bonnefond, Amélie; Fontés, Ghislaine; Philippe, Julien; Meur, Gargi; Diraison, Frédérique; Sessions, Richard B.; Rutter, Jared; Poitout, Vincent; Froguel, Philippe; Rutter, Guy A.

doi:10.1074/jbc.m111.254995

Cited by 23 publications

(26 citation statements)

References 35 publications

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“…By performing a cycloheximide chase experiment, here we found that PDX-1 protein stability was enhanced in MIN6 cells overexpressing WT hPASK but not the KD form in both MIN6 cells and isolated rat islets. Consistent with previous data (24,26), overexpression of WT hPASK did not affect PDX-1 mRNA expression (data not shown), consistent with a mainly posttranslational effect. Importantly, overexpression of KD GSK3␤ blocked PDX-1 degradation in cells overexpressing KD PASK, thus demonstrating the requirement for GSK3␤ in PASK regulation of PDX-1 stability.…”

Section: Discussionsupporting

confidence: 81%

“…Importantly, however, PASK mRNA levels are reduced and are no longer responsive to glucose in islets from type 2 diabetic humans (35). Recently, we have identified two rare mutations in the pask gene associated with early onset diabetes (26). One of these induced an ϳ2-fold increase in PASK activity, and its expression in islets increased basal insulin secretion and gene expression, supporting an important role for PASK in human ␤-cell function.…”

Section: Discussionmentioning

confidence: 98%

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Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells

Semache¹,

Zarrouki

Fontés³

et al. 2013

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells

Semache¹,

Zarrouki

Fontés³

et al. 2013

Journal of Biological Chemistry

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“…The deregulation of these signalling pathways might be involved in the development of obesity and type 2 diabetes. A mutation in the PASK gene has been described in the early onset of diabetes, which modulates glucose-stimulated insulin secretion [43]. A decrease in PASK expression was also found in pancreatic islets from human with type 2 diabetes [8].…”

Section: Discussionmentioning

confidence: 99%

PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

et al. 2014

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The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity.We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/refeeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and the anorexigenic properties of exendin-4 were significantly reduced, suggesting that PASK could be a mediator in the GLP-1 signalling pathway. Our data indicated that the PASK function could be critical for preserving the nutrient effect on AMPK and mTOR/S6K1 pathways and maintain the regulatory role of exendin-4 in food intake. Some of the antidiabetogenic effects of exendin-4 might be modulated through these processes. Abstract The complications caused by overweight, obesity and type 2 diabetes are one of the main problems that increase morbidity and mortality in developed countries. Hypothalamic metabolic sensors play an important role in the control of feeding and energy homeostasis. PAS kinase (PASK) is a nutrient sensor proposed as a regulator of glucose metabolism and cellular energy. The role of PASK might be similar to other known metabolic sensors, such as AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). PASK-deficient mice resist diet-induced obesity. We have recently reported that AMPK and mTOR/S6K1 pathways are regulated in the ventromedial and lateral hypothalamus in response to nutritional states, being modulated by anorexigenic glucagon-like peptide-1 (GLP-1)/exendin-4 in lean and obese rats. We identified PASK in hypothalamic areas, and its expression was regulated under fasting/refeeding conditions and modulated by exendin-4. Furthermore, PASK-deficient mice have an impaired activation response of AMPK and mTOR/S6K1 pathways. Thus, hypothalamic AMPK and S6K1 were highly activated under fasted/re-fed conditions. Additionally, in this study, we have observed that the exendin-4 regulatory effect in the activity of metabolic sensors was lost in PASK-deficient mice, and th...

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“…Thus, the mutated PASK (G1117E) has ~25 % higher activity than wild-type PASK and overexpression of this kinase variant led to a left-shift in the glucose response in mouse pancreatic islets. As a result, glucose-stimulated insulin secretion and insulin gene expression were increased at normally non-permissive (3 mM) glucose concentrations (72).…”

Section: Pas Domain Containing Protein Kinase (Pask)mentioning

confidence: 99%

“…Importantly, PASK expression is lower in the cells of patients with type 2 diabetes in comparison to cells of non-diabetic individuals (49). Very recently, an activating mutation in PASK was identified which is associated with non-autoimmune early-onset diabetes in humans (72). However, this mutant did not fully co-segregate with the disease and appears to serve as a modifier for a separate disease-causing mutation in another gene.…”

Section: Pas Domain Containing Protein Kinase (Pask)mentioning

confidence: 99%

Protein Kinases and Pancreatic Islet Function

Xavier¹

2012

Protein Kinases

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Human Mutation within Per-Arnt-Sim (PAS) Domain-containing Protein Kinase (PASK) Causes Basal Insulin Hypersecretion

Cited by 23 publications

References 35 publications

Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells

Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells

PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

Protein Kinases and Pancreatic Islet Function

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