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1.
The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway.
Wu, A, Wolley, M, Stowasser, M
Journal of human hypertension. 2019;(7):508-523
Abstract
Renal salt handling has a profound effect on body fluid and blood pressure (BP) maintenance as exemplified by the use of diuretic medications to treat states of volume expansion or hypertension. It has recently been proposed that a low potassium (K+) intake turns on a "renal K+ switch" which increases sodium (Na+) and chloride (Cl-) reabsorption, causing salt-retention, and in susceptible individuals, this causes hypertension. A signaling network, involving with-no-lysine (WNK) kinases, underpins the switch activity to coordinate aldosterone's two essential actions (K+ secretion and Na+ retention). A dysfunctional WNK kinase network drives excessive and inappropriate Na+, Cl- and urinary K+ retention in familial hyperkalemic hypertension (FHHt, also known as Gordon's syndrome). Mutations in genes encoding WNK1 and WNK4 or components of an ubiquitin ligase complex, cullin3, and kelch-like family member 3 (KLHL3), cause FHHt by upregulating the thiazide-sensitive sodium chloride cotransporter (NCC). Inhibition of NCC with thiazide diuretics corrects hypertension and hyperkalaemia in FHHt. These observations highlight the critical role of the NCC in the regulation of Na+ and K+ balance and of BP. Here we discuss the physiology of Na+ and K+ handling in the distal renal tubule with respect to BP regulation, with a focus on recent discoveries in the WNK- Ste20-related proline-alanine-rich kinase (SPAK)-NCC pathway.
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Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging.
Falcón, P, Escandón, M, Brito, Á, Matus, S
Oxidative medicine and cellular longevity. 2019;:5730532
Abstract
Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.
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The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1.
Xu, X, Chen, Y, Fu, Q, Ni, D, Zhang, J, Li, X, Lu, S
Journal of enzyme inhibition and medicinal chemistry. 2019;(1):361-374
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Abstract
Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity. Targeting allosteric PIF-pocket of PDK1 has become the focus of recent attention. In this review, we summarise the current advances in the structure-based discovery of PDK1 allosteric modulators. We will first present the three-dimensional structure of PDK1 and illustrate the allosteric regulatory mechanism of PDK1 through the modulation of the PIF-pocket. Then, the recent advances of PDK1 allosteric modulators targeting the PIF-pocket will be recapitulated detailly according to the structural similarity of allosteric modulators.
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4.
Greatwall kinase at a glance.
Castro, A, Lorca, T
Journal of cell science. 2018;(20)
Abstract
Mitosis is controlled by a subtle balance between kinase and phosphatase activities that involve the master mitotic kinase cyclin-B-Cdk1 and its antagonizing protein phosphatase 2A-B55 (PP2A-B55). Importantly, the Greatwall (Gwl; known as Mastl in mammals, Rim15 in budding yeast and Ppk18 in fission yeast) kinase pathway regulates PP2A-B55 activity by phosphorylating two proteins, cAMP-regulated phosphoprotein 19 (Arpp19) and α-endosulfine (ENSA). This phosphorylation turns these proteins into potent inhibitors of PP2A-B55, thereby promoting a correct timing and progression of mitosis. In this Cell Science at a Glance article and the accompanying poster, we discuss how Gwl is regulated in space and time, and how the Gwl-Arpp19-ENSA-PP2A-B55 pathway plays an essential role in the control of M and S phases from yeast to human. We also summarize how Gwl modulates oncogenic properties of cells and how nutrient deprivation influences Gwl activity.
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Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a novel TGFBR2 mutation.
Valenzuela, I, Fernández-Alvarez, P, Munell, F, Sanchez-Montanez, A, Giralt, G, Vendrell, T, Tizzano, EF
European journal of medical genetics. 2017;(6):303-307
Abstract
Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.
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DRD2: Bridging the Genome and Ingestive Behavior.
Sun, X, Luquet, S, Small, DM
Trends in cognitive sciences. 2017;(5):372-384
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Abstract
Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) has a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual, and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling, leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. Here, we consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene × environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on DA receptor subtype 2 (DRD2) signaling.
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Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis.
Patel, SH, Camargo, FD, Yimlamai, D
Gastroenterology. 2017;(3):533-545
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Abstract
The Hippo signaling pathway, also known as the Salvador-Warts-Hippo pathway, is a regulator of organ size. The pathway takes its name from the Drosophila protein kinase, Hippo (STK4/MST1 and STK3/MST2 in mammals), which, when inactivated, leads to considerable tissue overgrowth. In mammals, MST1 and MST2 negatively regulate the transcriptional co-activators yes-associated protein 1 and WW domain containing transcription regulator 1 (WWTR1/TAZ), which together regulate expression of genes that control proliferation, survival, and differentiation. Yes-associated protein 1 and TAZ activation have been associated with liver development, regeneration, and tumorigenesis. How their activity is dynamically regulated in these contexts is just beginning to be elucidated. We review the mechanisms of Hippo signaling in the liver and explore outstanding questions for future research.
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Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Freischmidt, A, Müller, K, Ludolph, AC, Weishaupt, JH, Andersen, PM
JAMA neurology. 2017;(1):110-113
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative syndromes that occur sporadically or have been associated with mostly dominant inheritance of mutations in more than 30 genes. A critical issue is whether all reported mutations are disease causing or are coincidental findings. In this review we analyze the pathogenicity of nonsynonymous variants in the newly discovered gene encoding TANK-binding kinase 1 (TBK1). The available data suggest that mutations in TBK1 that cause a 50% reduction of TBK1 protein levels are pathogenic. In most cases, the almost complete loss of expression of the mutated TBK1 allele is due to loss-of-function mutations creating a premature termination codon and the degradation of the mutated messenger RNA by nonsense-mediated messenger RNA decay. In addition, TBK1 protein levels reduced by 50% have been proven for specific in-frame deletions of 1 or several amino acids, probably due to increased degradation of the mutated protein. Evaluation of many of the TBK1 missense mutations found in patients with ALS or FTD is prevented by missing data demonstrating cosegregation of the variants and incomplete knowledge about the TBK1 functions relevant for neurodegeneration. These findings suggest that haploinsufficiency of TBK1 is causative for ALS and FTD regardless of the type of mutation. Evaluation of TBK1 variants that do not cause haploinsufficiency is not possible without data demonstrating cosegregation.
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YAP/TAZ-mediated activation of serine metabolism and methylation regulation is critical for LKB1-deficient breast cancer progression.
Wu, Q, Li, J, Sun, S, Chen, X, Zhang, H, Li, B, Sun, S
Bioscience reports. 2017;(5)
Abstract
The crucial interplay between metabolic remodeling and the epigenetics could contribute to promote cancer progression. A remarkable association within interaction, LKB1 has been reported, suggesting that the expression of key enzymes involving de novo serine synthesis and DNA methyltransferases like DNMT1 and DNMT3A increase LKB1-deficiency cells. However, the complex interactional link between metabolic remodeling and the epigenetics is still unclear. Hence, we focus on the relationship between YAP/TAZ and serine metabolism to control methylation of DNA or histone in breast cancer with LKB1 deficiency. We hypothesize that YAP/TAZ may have the function to activate key enzymes involving serine metabolism like PSPH and up-regulate the amino acid transporters to supply sources of serine synthesis through activation of C-MYC with TEAD1. Further, we speculate that YAP/TAZ in dependent of FOS may promote DNMT1 and subsequently mediate DNMT1-G9A complex involving serine metabolism and the methylation of DNA and histone. We hope that our study will stimulate further studies and a new targeted therapy and early medical intervention for YAP/TAZ could be a useful option for breast cancer cases complicated with LKB1 deficiency.
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Two Liters a Day Keep the Doctor Away? Considerations on the Pathophysiology of Suboptimal Fluid Intake in the Common Population.
Lang, F, Guelinckx, I, Lemetais, G, Melander, O
Kidney & blood pressure research. 2017;(3):483-494
Abstract
Suboptimal fluid intake may require enhanced release of antidiuretic hormone (ADH) or vasopressin for the maintenance of adequate hydration. Enhanced copeptin levels (reflecting enhanced vasopressin levels) in 25% of the common population are associated with enhanced risk of metabolic syndrome with abdominal obesity, type 2 diabetes, hypertension, coronary artery disease, heart failure, vascular dementia, cognitive impairment, microalbuminuria, chronic kidney disease, inflammatory bowel disease, cancer, and premature mortality. Vasopressin stimulates the release of glucocorticoids which in turn up-regulate the serum- and glucocorticoid-inducible kinase 1 (SGK1). Moreover, dehydration upregulates the transcription factor NFAT5, which in turn stimulates SGK1 expression. SGK1 is activated by insulin, growth factors and oxidative stress via phosphatidylinositide-3-kinase, 3-phosphoinositide-dependent kinase PDK1 and mTOR. SGK1 is a powerful stimulator of Na+/K+-ATPase, carriers (e.g. the Na+,K+,2Cl- cotransporter NKCC, the NaCl cotransporter NCC, the Na+/H+ exchanger NHE3, and the Na+ coupled glucose transporter SGLT1), and ion channels (e.g. the epithelial Na+ channel ENaC, the Ca2+ release activated Ca2+ channel Orai1 with its stimulator STIM1, and diverse K+ channels). SGK1 further participates in the regulation of the transcription factors nuclear factor kappa-B NFκB, p53, cAMP responsive element binding protein (CREB), activator protein-1, and forkhead transcription factor FKHR-L1 (FOXO3a). Enhanced SGK1 activity fosters the development of hypertension, obesity, diabetes, thrombosis, stroke, inflammation including inflammatory bowel disease and autoimmune disease, cardiac fibrosis, proteinuria, renal failure as well as tumor growth. The present brief review makes the case that suboptimal fluid intake in the common population may enhance vasopressin and glucocorticoid levels thus up-regulating SGK1 expression and favouring the development of SGK1 related pathologies.