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https://www.readbyqxmd.com/read/28282258/wnk1-is-an-unexpected-autophagy-inhibitor
#1
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
Autophagy is a cellular degradation pathway that is essential to maintain cellular physiology, and deregulation of autophagy leads to multiple diseases in humans. In a recent study, we discovered that the protein kinase WNK1 (WNK lysine deficient protein kinase 1) is an inhibitor of autophagy. The loss of WNK1 increases both basal and starvation-induced autophagy. In addition, the depletion of WNK1 increases the activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which is required to induce autophagy...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28178566/wnk-kinase-signaling-in-ion-homeostasis-and-human-disease
#2
REVIEW
Masoud Shekarabi, Jinwei Zhang, Arjun R Khanna, David H Ellison, Eric Delpire, Kristopher T Kahle
WNK kinases, along with their upstream regulators (CUL3/KLHL3) and downstream targets (the SPAK/OSR1 kinases and the cation-Cl(-) cotransporters [CCCs]), comprise a signaling cascade essential for ion homeostasis in the kidney and nervous system. Recent work has furthered our understanding of the WNKs in epithelial transport, cell volume homeostasis, and GABA signaling, and uncovered novel roles for this pathway in immune cell function and cell proliferation.
February 7, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28096417/phosphorylation-by-pkc-and-pka-regulate-the-kinase-activity-and-downstream-signaling-of-wnk4
#3
Maria Castañeda-Bueno, Juan Pablo Arroyo, Junhui Zhang, Jeremy Puthumana, Orlando Yarborough, Shigeru Shibata, Lorena Rojas-Vega, Gerardo Gamba, Jesse Rinehart, Richard P Lifton
With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28004876/towards-the-development-of-small-molecule-mo25-binders-as-potential-indirect-spak-osr1-kinase-inhibitors
#4
Hachemi Kadri, Mubarak A Alamri, Iva H Navratilova, Luke J Alderwick, Nigel S Simpkins, Youcef Mehellou
The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100-fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in-house library of ≈4000 compounds...
December 22, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28003191/calcineurin-inhibitor-cyclosporine-a-activates-renal-na-k-cl-cotransporters-via-local-and-systemic-mechanisms
#5
Katharina Ilse Blankenstein, Aljona Borschewski, Robert Labes, Alexander Paliege, Christin Boldt, James A McCormick, David H Ellison, Michael Bader, Sebastian Bachmann, Kerim Mutig
Calcineurin dephosphorylates NFAT transcription factors, thereby facilitating T-cell mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation, but may cause side effects including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA)...
December 21, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27983989/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#6
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
October 28, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27942049/potassium-depletion-stimulates-na-cl-cotransporter-via-phosphorylation-and-inactivation-of-the-ubiquitin-ligase-kelch-like-3
#7
Kenichi Ishizawa, Ning Xu, Johannes Loffing, Richard P Lifton, Toshiro Fujita, Shunya Uchida, Shigeru Shibata
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K(+) intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K(+)-mediated activation of Na-Cl cotransporter (NCC) in the kidney...
2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27853306/osr1-and-spak-cooperatively-modulate-sertoli-cell-support-of-mouse-spermatogenesis
#8
Yung-Liang Liu, Sung-Sen Yang, Shyi-Jou Chen, Yu-Chun Lin, Chin-Chen Chu, Hsin-Hui Huang, Fung-Wei Chang, Mu-Hsien Yu, Shih-Hua Lin, Gwo-Jang Wu, Huey-Kang Sytwu
We investigated the role of oxidative stress-responsive kinase-1 (OSR1) and STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK), upstream regulators of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1)-essential for spermatogenesis-in mouse models of male fertility. Global OSR1(+/-) gene mutations, but not global SPAK(-/-) or Sertoli cell (SC)-specific OSR1 gene knockout (SC-OSR1(-/-)), cause subfertility with impaired sperm function and are associated with reduced abundance of phosphorylated (p)-NKCC1 but increased p-SPAK expression in testicular tissue and spermatozoa...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27805568/hand2-inhibits-kidney-specification-while-promoting-vein-formation-within-the-posterior-mesoderm
#9
Elliot A Perens, Zayra V Garavito-Aguilar, Gina P Guio-Vega, Karen T Peña, Yocheved L Schindler, Deborah Yelon
Proper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. Here, we show that the bHLH transcription factor Hand2 limits the size of the embryonic kidney by restricting IM dimensions. The IM is expanded in zebrafish hand2 mutants and is diminished when hand2 is overexpressed. Within the posterior mesoderm, hand2 is expressed laterally adjacent to the IM...
November 2, 2016: ELife
https://www.readbyqxmd.com/read/27782156/identification-and-validation-of-candidate-epigenetic-biomarkers-in-lung-adenocarcinoma
#10
Iben Daugaard, Diana Dominguez, Tina E Kjeldsen, Lasse S Kristensen, Henrik Hager, Tomasz K Wojdacz, Lise Lotte Hansen
Lung cancer is the number one cause of cancer-related deaths worldwide. DNA methylation is an epigenetic mechanism that regulates gene expression, and disease-specific methylation changes can be targeted as biomarkers. We have compared the genome-wide methylation pattern in tumor and tumor-adjacent normal lung tissue from four lung adenocarcinoma (LAC) patients using DNA methylation microarrays and identified 74 differentially methylated regions (DMRs). Eighteen DMRs were selected for validation in a cohort comprising primary tumors from 52 LAC patients and tumor-adjacent normal lung tissue from 32 patients by methylation-sensitive high resolution melting (MS-HRM) analysis...
October 26, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27457700/extracellular-k-rapidly-controls-nacl-cotransporter-phosphorylation-in-the-native-distal-convoluted-tubule-by-cl-dependent-and-independent-mechanisms
#11
David Penton, Jan Czogalla, Agnieszka Wengi, Nina Himmerkus, Dominique Loffing-Cueni, Monique Carrel, Renuga Devi Rajaram, Olivier Staub, Markus Bleich, Frank Schweda, Johannes Loffing
KEY POINTS: High dietary potassium (K(+) ) intake dephosphorylates and inactivates the NaCl cotransporter (NCC) in the renal distal convoluted tubule (DCT). Using several ex vivo models, we show that physiological changes in extracellular K(+) , similar to those occurring after a K(+) rich diet, are sufficient to promote a very rapid dephosphorylation of NCC in native DCT cells. Although the increase of NCC phosphorylation upon decreased extracellular K(+) appears to depend on cellular Cl(-) fluxes, the rapid NCC dephosphorylation in response to increased extracellular K(+) is not Cl(-) -dependent...
November 1, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27442016/osr1-interacts-synergistically-with-wt1-to-regulate-kidney-organogenesis
#12
Jingyue Xu, Han Liu, Ok Hee Chai, Yu Lan, Rulang Jiang
Renal hypoplasia is a common cause of pediatric renal failure and several adult-onset diseases. Recent studies have associated a variant of the OSR1 gene with reduction of newborn kidney size and function in heterozygotes and neonatal lethality with kidney defects in homozygotes. How OSR1 regulates kidney development and nephron endowment is not well understood, however. In this study, by using the recently developed CRISPR genome editing technology, we genetically labeled the endogenous Osr1 protein and show that Osr1 interacts with Wt1 in the developing kidney...
2016: PloS One
https://www.readbyqxmd.com/read/27322883/the-regulation-of-na-cl-cotransporter-by-with-no-lysine-kinase-4
#13
Eduardo R Argaiz, Gerardo Gamba
PURPOSE OF REVIEW: Abundant evidence supports that the NaCl cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4. RECENT FINDINGS: Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC...
September 2016: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27268962/maize-and-arabidopsis-argos-proteins-interact-with-ethylene-receptor-signaling-complex-supporting-a-regulatory-role-for-argos-in-ethylene-signal-transduction
#14
Jinrui Shi, Bruce J Drummond, Hongyu Wang, Rayeann L Archibald, Jeffrey E Habben
The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown...
2016: Plant Physiology
https://www.readbyqxmd.com/read/27261090/mitogen-activated-protein-kinases-as-key-players-in-osmotic-stress-signaling
#15
REVIEW
Xiangyu Zhou, Isao Naguro, Hidenori Ichijo, Kengo Watanabe
BACKGROUND: Osmotic stress arises from the difference between intracellular and extracellular osmolality. It induces cell swelling or shrinkage as a consequence of water influx or efflux, which threatens cellular activities. Mitogen-activated protein kinases (MAPKs) play central roles in signaling pathways in osmotic stress responses, including the regulation of intracellular levels of inorganic ions and organic osmolytes. SCOPE OF REVIEW: The present review summarizes the cellular osmotic stress response and the function and regulation of the vertebrate MAPK signaling pathways involved...
September 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27213811/establishment-of-a-conditionally-immortalized-wilms-tumor-cell-line-with-a-homozygous-wt1-deletion-within-a-heterozygous-11p13-deletion-and-upd-limited-to-11p15
#16
Artur Brandt, Katharina Löhers, Manfred Beier, Barbara Leube, Carmen de Torres, Jaume Mora, Parineeta Arora, Parmjit S Jat, Brigitte Royer-Pokora
We describe a stromal predominant Wilms tumor with focal anaplasia and a complex, tumor specific chromosome 11 aberration: a homozygous deletion of the entire WT1 gene within a heterozygous 11p13 deletion and an additional region of uniparental disomy (UPD) limited to 11p15.5-p15.2 including the IGF2 gene. The tumor carried a heterozygous p.T41A mutation in CTNNB1. Cells established from the tumor carried the same chromosome 11 aberration, but a different, homozygous p.S45Δ CTNNB1 mutation. Uniparental disomy (UPD) 3p21...
2016: PloS One
https://www.readbyqxmd.com/read/27122160/the-ste20-kinases-spak-and-osr1-travel-between-cells-through-exosomes
#17
Rainelli Koumangoye, Eric Delpire
Proteomics studies have identified Ste20-related proline/alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) in exosomes isolated from body fluids such as blood, saliva, and urine. Because proteomics studies likely overestimate the number of exosome proteins, we sought to confirm and extend this observation using traditional biochemical and cell biology methods. We utilized HEK293 cells in culture to verify the packaging of these Ste20 kinases in exosomes. Using a series of centrifugation and filtration steps of conditioned culture medium isolated from HEK293 cells, we isolated nanovesicles in the range of 40-100 nm...
July 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27119824/osr1-and-spak-sensitivity-of-large-conductance-ca2-activated-k-channel
#18
Bernat Elvira, Yogesh Singh, Jamshed Warsi, Carlos Munoz, Florian Lang
BACKGROUND/AIMS: The oxidative stress-responsive kinase 1 (OSR1) and the serine/threonine kinases SPAK (SPS1-related proline/alanine-rich kinase) are under the control of WNK (with-no-K [Lys]) kinases. OSR1 and SPAK participate in diverse functions including cell volume regulation and neuronal excitability. Cell volume and neuronal excitation are further modified by the large conductance Ca2+-activated K+ channels (maxi K+ channel or BK channels). An influence of OSR1 and/or SPAK on BK channel activity has, however, never been shown...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27101813/novel-round-cells-in-urine-sediment-and-their-clinical-implications
#19
Kenichi Shukuya, Sayoko Ogura, Yasunori Tokuhara, Shigeo Okubo, Yutaka Yatomi, Minoru Tozuka, Tatsuo Shimosawa
BACKGROUND: Voided urine contains a variety of cells from the kidney and urinary tract and urinalysis provides us various information by investigating cellular components. We investigated urine sediment from renal impaired patients. RESULTS: We found 'round cell' to be distinct from known cells in sediment and is close to proximal convoluted tubule-derived cells based on morphology and molecular marker expression (GGT1 but not podocalyxin). Also it was positive for undifferentiated cell markers, including PAX2, WT1, OSR1, and SIX2...
June 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/27076645/the-cul3-klhl3-wnk-spak-osr1-pathway-as-a-target-for-antihypertensive-therapy
#20
Mohammed Z Ferdaus, James A McCormick
Chronic high blood pressure (hypertension) is the most common disease in the Unites States. While several classes of drugs exist to treat it, many patients (up to 10 million Americans) respond poorly to therapy, even when multiple classes are used. Recent evidence suggests that a significant portion of patients will always remain hypertensive despite maximum therapy with the drugs currently available. Therefore, there is a pressing need to develop novel antihypertensive agents. One limitation has been the identification of new targets, a limitation that has been overcome by recent insights into the mechanisms underlying monogenic forms of hypertension...
June 1, 2016: American Journal of Physiology. Renal Physiology
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