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Kristi J Warren, Xi Fang, Nagaraj M Gowda, Joshua J Thompson, Nicola M Heller
Lung M2 macrophages are regulators of airway inflammation, associated with poor lung function in allergic asthma. Previously, we demonstrated that IL-4-induced M2 gene expression correlated with tyrosine phosphorylation of the insulin receptor substrate (IRS)-2 in macrophages. We hypothesized that negative regulation of IRS-2 activity following IL-4 stimulation is dependent upon serine phosphorylation of IRS-2. Herein, we describe an inverse relationship between tyrosine phosphorylation (pY) and serine phosphorylation (pS) of IRS-2 following IL-4 stimulation...
October 14, 2016: Journal of Biological Chemistry
Sisley Austin, Saïd Taouji, Eric Chevet, Harald Wodrich, Fabienne Rayne
AlphaScreen(®) is a technology particularly suitable for bi-molecular inhibitor screening assays, e.g. using protein-protein interactions with purified recombinant proteins. Each binding partner of the bi-molecular interaction is coupled either to donor or to acceptor beads. The technology is based on the quantifiable transfer of oxygen singlets from donor to acceptor microbeads brought together by a specific interaction between the partners. We identified the conserved interaction between WW domains of cellular ubiquitin ligases of the Nedd4 family and a short peptide motif (PPxY) present in several structural and non-structural viral proteins as a potential drug target...
2016: Methods in Molecular Biology
Sudhirkumar Yanpallewar, Ting Wang, Dawn C I Koh, Eros Quarta, Gianluca Fulgenzi, Lino Tessarollo
Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions...
2016: Scientific Reports
Adrián Galiana-Simal, Elena Olivares-Álvaro, Mercedes Klett-Mingo, María Belén Ruiz-Roso, Sandra Ballesteros, Natalia de Las Heras, Peter J Fuller, Vicente Lahera, Beatriz Martín-Fernández
Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na(+) channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats...
August 14, 2016: Journal of Nutritional Biochemistry
Fredrick J Rosario, Theresa L Powell, Thomas Jansson
Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms...
2016: Scientific Reports
KimberlyD Mackenzie, Natalie J Foot, Sushma Anand, Hazel E Dalton, Natasha Chaudhary, Brett M Collins, Suresh Mathivanan, Sharad Kumar
The release of extracellular vesicles (EVs) is important for both normal physiology and disease. However, a basic understanding of the targeting of EV cargoes, composition and mechanism of release is lacking. Here we present evidence that the divalent metal ion transporter (DMT1) is unexpectedly regulated through release in EVs. This process involves the Nedd4-2 ubiquitin ligase, and the adaptor proteins Arrdc1 and Arrdc4 via different budding mechanisms. We show that mouse gut explants release endogenous DMT1 in EVs...
2016: Cell Discovery
Begoña Anta, Carlos Martín-Rodríguez, Carolina Gomis-Perez, Laura Calvo, Saray López-Benito, Andrés A Calderón-García, Cristina Vicente-García, Álvaro Villarroel, Juan C Arévalo
Ubiquitination of the TrkA neurotrophin receptor in response to NGF is critical in the regulation of TrkA activation and functions. TrkA is ubiquitinated, among other E3 ubiquitin ligases, by Nedd4-2. To understand mechanistically how TrkA ubiquitination is regulated, we performed a siRNA screening to identify deubiquitinating enzymes and found that USP36 acts as an important regulator of TrkA activation kinetics and ubiquitination. However, USP36 action on TrkA was indirect because it does not deubiquitinate TrkA...
September 2, 2016: Journal of Biological Chemistry
Kamindla Rajesh, Jothilatha Krishnamoorthy, Jyotsana Gupta, Urszula Kazimierczak, Andreas I Papadakis, Zhilin Deng, Shuo Wang, Shinji Kuninaka, Antonis E Koromilas
The HIPPO pathway is an evolutionary conserved regulator of organ size that controls both cell proliferation and death. This pathway has an important role in mediating cell death in response to oxidative stress through the inactivation of Yes-associated protein (YAP) and inhibition of anti-oxidant gene expression. Cells exposed to oxidative stress induce the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to the general inhibition of mRNA translation initiation...
July 7, 2016: Oncotarget
S M Lamothe, S Zhang
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal, and smooth muscle cells, neurons, and endocrine cells. Their dysfunction underlies the pathology of various diseases. Thus, the tight regulation of these transmembrane proteins is essential for cell physiology. While the ubiquitin system is involved in many aspects of cellular processes, this chapter focuses on the ubiquitin-mediated degradation of ion channels and transporters. Ubiquitination of ion channels and transporters is multifaceted and occurs at various cellular compartments such as the plasma membrane and the endoplasmic reticulum...
2016: Progress in Molecular Biology and Translational Science
Shintaro Minegishi, Tomoaki Ishigami, Tabito Kino, Lin Chen, Rie Nakashima-Sasaki, Naomi Araki, Keisuke Yatsu, Megumi Fujita, Satoshi Umemura
Epithelial sodium channels (ENaCs) play critical roles in the maintenance of fluid and electrolyte homeostasis, and their genetic abnormalities cause one type of hereditary salt-sensitive hypertension, Liddle syndrome. As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal. Nedd4L/Nedd4-2 isoforms with a C2 domain are hypothesized to be related closely to ubiquitination of ENaCs. We generated Nedd4-2 C2 domain knockout mice...
2016: Scientific Reports
Patricio Vélez, Austin B Schwartz, Subashini R Iyer, Anthony Warrington, Debra Ann Fadool
Voltage-dependent potassium channels (Kv) go beyond the stabilization of the resting potential and regulate biochemical pathways, regulate intracellular signaling, and detect energy homeostasis. Because targeted deletion and pharmacological block of the Kv1.3 channel protein produce marked changes in metabolism, resistance to diet-induced obesity, and changes in olfactory structure and function, this investigation explored Nedd4-2-mediated ubiquitination and degradation to regulate Kv1.3 channel density. Heterologous coexpression of Nedd4-2 ligase and Kv1...
August 1, 2016: Journal of Neurophysiology
Allison E Norlander, Mohamed A Saleh, Nikhil V Kamat, Benjamin Ko, Juan Gnecco, Linjue Zhu, Bethany L Dale, Yoichiro Iwakura, Robert S Hoover, Alicia A McDonough, Meena S Madhur
Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent...
July 2016: Hypertension
Koichi Inoue, Tiandong Leng, Tao Yang, Zhao Zeng, Takatoshi Ueki, Zhi-Gang Xiong
Increased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) can be induced by stress and growth factors in mammals, and plays an important role in cancer, diabetes, and hypertension. A recent work suggested that SGK1 activity restores damage in a stroke model. To further investigate the role of SGKs in ischemic brain injury, we examined how SGK inhibitors influence stroke outcome in vivo and neurotoxicity in vitro. Infarct volumes were compared in adult mice with middle cerebral artery occlusion, followed by 24 h reperfusion, in the absence or presence of SGK inhibitors...
July 2016: Journal of Neurochemistry
Ignacio Ibáñez, F Javier Díez-Guerra, Cecilio Giménez, Francisco Zafra
GLT-1 is the main glutamate transporter in the brain and undergoes trafficking processes that control its concentration on the cell surface thereby shaping glutamatergic neurotransmission. We have investigated how the traffic of GLT-1 is regulated by transporter activity. We report that internalization of GLT-1 from the cell surface is accelerated by transportable substrates like glutamate or aspartate, as well as by the transportable inhibitor L-trans-2,4-PDC, but not by the non-substrate inhibitor WAY 213613 in primary mixed cultures and in transiently transfected HEK293 cells...
August 2016: Neuropharmacology
Hao Wang, Ruo-Qiong Sun, Daria Camera, Xiao-Yi Zeng, Eunjung Jo, Stanley M H Chan, Terence P Herbert, Juan C Molero, Ji-Ming Ye
The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy...
July 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Lama Al-Qusairi, Denis Basquin, Ankita Roy, Matteo Stifanelli, Renuga Devi Rajaram, Anne Debonneville, Izabela Nita, Marc Maillard, Johannes Loffing, Arohan R Subramanya, Olivier Staub
The stimulation of postprandial K(+) clearance involves aldosterone-independent and -dependent mechanisms. In this context, serum- and glucocorticoid-induced kinase (SGK)1, a ubiquitously expressed kinase, is one of the primary aldosterone-induced proteins in the aldosterone-sensitive distal nephron. Germline inactivation of SGK1 suggests that this kinase is fundamental for K(+) excretion under conditions of K(+) load, but the specific role of renal SGK1 remains elusive. To avoid compensatory mechanisms that may occur during nephrogenesis, we used inducible, nephron-specific Sgk1(Pax8/LC1) mice to assess the role of renal tubular SGK1 in K(+) regulation...
August 1, 2016: American Journal of Physiology. Renal Physiology
Kathryn A Jewett, Catherine A Christian, Jonathan T Bacos, Kwan Young Lee, Jiuhe Zhu, Nien-Pei Tsai
BACKGROUND: Neural network synchrony is a critical factor in regulating information transmission through the nervous system. Improperly regulated neural network synchrony is implicated in pathophysiological conditions such as epilepsy. Despite the awareness of its importance, the molecular signaling underlying the regulation of neural network synchrony, especially after stimulation, remains largely unknown. RESULTS: In this study, we show that elevation of neuronal activity by the GABA(A) receptor antagonist, Picrotoxin, increases neural network synchrony in primary mouse cortical neuron cultures...
2016: Molecular Brain
Yuan Huang, Zhijie Wang, Yinan Liu, Hongbo Xiong, Yuanyuan Zhao, Ling Wu, Chao Yuan, Longfei Wang, Yuxi Hou, Gang Yu, Zhengrong Huang, Chengqi Xu, Qiuyun Chen, Qing K Wang
Nav1.5, the pore-forming α subunit of the cardiac voltage-gated Na(+) channel complex, is required for the initiation and propagation of the cardiac action potential. Mutations in Nav1.5 cause cardiac arrhythmias and sudden death. The cardiac Na(+) channel functions as a protein complex; however, its complete components remain to be fully elucidated. A yeast two-hybrid screen identified a new candidate Nav1.5-interacting protein, αB-crystallin. GST pull-down, co-immunoprecipitation, and immunostaining analyses validated the interaction between Nav1...
May 20, 2016: Journal of Biological Chemistry
Musaab Ahmed, Myriam Fezai, Nestor L Uzcategui, Zohreh Hosseinzadeh, Florian Lang
BACKGROUND: The serum & glucocorticoid inducible kinase isoform SGK3 is a powerful regulator of several transporters, ion channels and the Na+/K+ ATPase. Targets of SGK3 include the ubiquitin ligase Nedd4-2, which is in turn a known regulator of the voltage gated K+ channel Kv1.5 (KCNA5). The present study thus explored whether SGK3 modifies the activity of the voltage gated K+ channel KCNA5, which participates in the regulation of diverse functions including atrial cardiac action potential, activity of vascular smooth muscle cells, insulin release and tumour cell proliferation...
2016: Cellular Physiology and Biochemistry
Da Xu, Haoxun Wang, Qiang Zhang, Guofeng You
Human organic anion transporter 1 (hOAT1) expressed at the membrane of the kidney proximal tubule cells mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and antiinflammatories. Therefore, understanding the regulation of hOAT1 will provide significant insights into kidney function and dysfunction. We previously established that hOAT1 transport activity is inhibited by activation of protein kinase C (PKC) through accelerating hOAT1 internalization from cell surface into intracellular endosomes and subsequent degradation...
May 1, 2016: American Journal of Physiology. Renal Physiology
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