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Developmental regulation of Wnt signaling by Nagk and the UDP-GlcNAc salvage pathway.
Neitzel LR, Spencer ZT, Nayak A, Cselenyi CS, Benchabane H, Youngblood CQ, Zouaoui A, Ng V, Stephens L, Hann T, Patton JG, Robbins D, Ahmed Y, Lee E
(2019) Mech Dev 156: 20-31
MeSH Terms: Animals, Body Patterning, Drosophila, Embryonic Development, Evolution, Molecular, Gene Expression Regulation, Developmental, Glycosylation, Humans, Phosphotransferases (Alcohol Group Acceptor), Wnt Signaling Pathway, Xenopus laevis, Zebrafish
Show Abstract · Added April 10, 2019
In a screen for human kinases that regulate Xenopus laevis embryogenesis, we identified Nagk and other components of the UDP-GlcNAc glycosylation salvage pathway as regulators of anteroposterior patterning and Wnt signaling. We find that the salvage pathway does not affect other major embryonic signaling pathways (Fgf, TGFβ, Notch, or Shh), thereby demonstrating specificity for Wnt signaling. We show that the role of the salvage pathway in Wnt signaling is evolutionarily conserved in zebrafish and Drosophila. Finally, we show that GlcNAc is essential for the growth of intestinal enteroids, which are highly dependent on Wnt signaling for growth and maintenance. We propose that the Wnt pathway is sensitive to alterations in the glycosylation state of a cell and acts as a nutritional sensor in order to couple growth/proliferation with its metabolic status. We also propose that the clinical manifestations observed in congenital disorders of glycosylation (CDG) in humans may be due, in part, to their effects on Wnt signaling during development.
Copyright © 2019 Elsevier B.V. All rights reserved.
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12 MeSH Terms
Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells.
Koumangoye R, Omer S, Delpire E
(2018) Am J Physiol Cell Physiol 315: C258-C276
MeSH Terms: Animals, Cell Membrane, Cells, Cultured, Colon, Cytoplasm, Dogs, Epithelial Cells, Female, Madin Darby Canine Kidney Cells, Male, Mice, Oocytes, Salivary Glands, Sodium-Potassium-Chloride Symporters, Sodium-Potassium-Exchanging ATPase, Solute Carrier Family 12, Member 2, Xenopus laevis
Show Abstract · Added May 4, 2018
We recently reported the case of a young patient with multisystem failure carrying a de novo mutation in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1 (NKCC1). Heterologous expression studies in nonepithelial cells failed to demonstrate dominant-negative effects. In this study, we examined expression of the mutant cotransporter in epithelial cells. Using Madin-Darby canine kidney (MDCK) cells grown on glass coverslips, permeabilized support, and Matrigel, we show that the fluorescently tagged mutant cotransporter is expressed in cytoplasm and at the apical membrane and affects epithelium integrity. Expression of the mutant transporter at the apical membrane also results in the mislocalization of some of the wild-type transporter to the apical membrane. This mistargeting is specific to NKCC1 as the Na-K-ATPase remains localized on the basolateral membrane. To assess transporter localization in vivo, we created a mouse model using CRISPR/cas9 that reproduces the 11 bp deletion in exon 22 of Slc12a2. Although the mice do not display an overt phenotype, we show that the colon and salivary gland expresses wild-type NKCC1 abundantly at the apical pole, confirming the data obtained in cultured epithelial cells. Enough cotransporter must remain, however, on the basolateral membrane to participate in saliva secretion, as no significant decrease in saliva production was observed in the mutant mice.
1 Communities
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17 MeSH Terms
Functional features of the "finger" domain of the DEG/ENaC channels MEC-4 and UNC-8.
Matthewman C, Johnson CK, Miller DM, Bianchi L
(2018) Am J Physiol Cell Physiol 315: C155-C163
MeSH Terms: Amino Acid Sequence, Animals, Calcium, Cell Death, Cell Membrane Permeability, Epithelial Sodium Channels, Magnesium, Membrane Proteins, Mutation, Oocytes, Protein Transport, Sodium, Xenopus laevis
Show Abstract · Added March 26, 2019
UNC-8 and MEC-4 are two members of the degenerin/epithelial Na channel (DEG/ENaC) family of voltage-independent Na channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations [UNC-8(d) and MEC-4(d)] that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations in mec-6. UNC-8 and MEC-4 differ functionally in three major ways: 1) MEC-4 is calcium permeable, whereas UNC-8 is not; 2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; and 3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8. We previously reported that Capermeability of MEC-4 is conferred by the second transmembrane domain. We show here that the extracellular "finger" domain of UNC-8 is sufficient to mediate inhibition by divalent cations and that regulation by MEC-6 also depends on this region. Thus, our work confirms that the finger domain houses residues involved in gating of this channel class and shows for the first time that the finger domain also mediates regulation by chaperone protein MEC-6. Given that the finger domain is the most divergent region across the DEG/ENaC family, we speculate that it influences channel trafficking and function in a unique manner depending on the channel subunit.
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13 MeSH Terms
Structural Mechanism of Functional Modulation by Gene Splicing in NMDA Receptors.
Regan MC, Grant T, McDaniel MJ, Karakas E, Zhang J, Traynelis SF, Grigorieff N, Furukawa H
(2018) Neuron 98: 521-529.e3
MeSH Terms: Animals, Cell Line, Female, HEK293 Cells, Humans, Insecta, Protein Splicing, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, N-Methyl-D-Aspartate, Xenopus laevis
Show Abstract · Added April 10, 2019
Alternative gene splicing gives rise to N-methyl-D-aspartate (NMDA) receptor ion channels with defined functional properties and unique contributions to calcium signaling in a given chemical environment in the mammalian brain. Splice variants possessing the exon-5-encoded motif at the amino-terminal domain (ATD) of the GluN1 subunit are known to display robustly altered deactivation rates and pH sensitivity, but the underlying mechanism for this functional modification is largely unknown. Here, we show through cryoelectron microscopy (cryo-EM) that the presence of the exon 5 motif in GluN1 alters the local architecture of heterotetrameric GluN1-GluN2 NMDA receptors and creates contacts with the ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, which are absent in NMDA receptors lacking the exon 5 motif. The unique interactions established by the exon 5 motif are essential to the stability of the ATD/LBD and LBD/LBD interfaces that are critically involved in controlling proton sensitivity and deactivation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.
Li B, Orton D, Neitzel LR, Astudillo L, Shen C, Long J, Chen X, Kirkbride KC, Doundoulakis T, Guerra ML, Zaias J, Fei DL, Rodriguez-Blanco J, Thorne C, Wang Z, Jin K, Nguyen DM, Sands LR, Marchetti F, Abreu MT, Cobb MH, Capobianco AJ, Lee E, Robbins DJ
(2017) Sci Signal 10:
MeSH Terms: Animals, Antineoplastic Agents, Benzoates, Casein Kinase Ialpha, Enzyme Activation, Enzyme Activators, Gene Expression Regulation, Neoplastic, HCT116 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Neoplasms, Organ Culture Techniques, Phosphorylation, Pyrvinium Compounds, Signal Transduction, Surface Plasmon Resonance, Wnt Proteins, Wnt Signaling Pathway, Xenograft Model Antitumor Assays, Xenopus laevis
Show Abstract · Added July 18, 2017
Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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24 MeSH Terms
Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain.
Romero-Hernandez A, Simorowski N, Karakas E, Furukawa H
(2016) Neuron 92: 1324-1336
MeSH Terms: 2-Hydroxyphenethylamine, Animals, Binding Sites, Blotting, Western, Crystallography, Hydrogen Bonding, Piperidines, Protein Structure, Quaternary, Receptors, N-Methyl-D-Aspartate, Sf9 Cells, Spodoptera, Xenopus laevis, Zinc
Show Abstract · Added April 3, 2018
Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.
Copyright © 2016 Elsevier Inc. All rights reserved.
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MeSH Terms
Reconstitution of the Cytoplasmic Regulation of the Wnt Signaling Pathway Using Xenopus Egg Extracts.
Hyde AS, Hang BI, Lee E
(2016) Methods Mol Biol 1481: 101-9
MeSH Terms: Animals, Cell Cycle, Chromatin Assembly and Disassembly, DNA Replication, Embryonic Development, Microtubules, Molecular Biology, Oocytes, Proteolysis, Wnt Proteins, Wnt Signaling Pathway, Xenopus laevis, beta Catenin
Show Abstract · Added February 13, 2017
The regulation of β-catenin turnover is the central mechanism governing activation of the Wnt signaling pathway. All components of the pathway are present in the early embryo of Xenopus laevis, and Xenopus egg extracts have been used to recapitulate complex biological reactions such as microtubule dynamics, DNA replication, chromatin assembly, and phases of the cell cycle. Herein, we describe a biochemical method for analyzing β-catenin degradation using radiolabeled and luciferase-fusion proteins in Xenopus egg extracts. We show that in such a biochemical system, cytoplasmic β-catenin degradation is regulated by soluble components of the Wnt pathway as well as small molecules.
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13 MeSH Terms
Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.
Rollins-Smith LA, Fites JS, Reinert LK, Shiakolas AR, Umile TP, Minbiole KP
(2015) Infect Immun 83: 4565-70
MeSH Terms: Adenosine, Animals, Apoptosis, Cell Survival, Chytridiomycota, Drug Synergism, Host-Pathogen Interactions, Humans, Jurkat Cells, Kynurenine, Lymphocytes, Mycoses, Skin, Thionucleosides, Tryptophan, Xenopus laevis
Show Abstract · Added April 18, 2017
Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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16 MeSH Terms
Modeling the roles of protein kinase Cβ and η in single-cell wound repair.
Holmes WR, Liao L, Bement W, Edelstein-Keshet L
(2015) Mol Biol Cell 26: 4100-8
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Models, Biological, Oocytes, Protein Kinase C, Protein Kinase C beta, Single-Cell Analysis, Wound Healing, Xenopus laevis, rho GTP-Binding Proteins
Show Abstract · Added February 26, 2016
Wounded cells such as Xenopus oocytes respond to damage by assembly and closure of an array of actin filaments and myosin-2 controlled by Rho GTPases, including Rho and Cdc42. Rho and Cdc42 are patterned around wounds in a characteristic manner, with active Rho concentrating in a ring-like zone inside a larger, ring-like zone of active Cdc42. How this patterning is achieved is unknown, but Rho and Cdc42 at wounds are subject to regulation by other proteins, including the protein kinases C. Specifically, Cdc42 and Rho activity are enhanced by PKCβ and inhibited by PKCη. We adapt a mathematical model of Simon and coworkers to probe the possible roles of these kinases. We show that PKCβ likely affects the magnitude of positive Rho-Abr feedback, whereas PKCη acts on Cdc42 inactivation. The model explains both qualitative and some overall quantitative features of PKC-Rho GTPase regulation. It also accounts for the previous, peculiar observation that ∼ 20% of cells overexpressing PKCη display zone inversions--that is, displacement of active Rho to the outside of the active Cdc42.
© 2015 Holmes, Liao, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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11 MeSH Terms
Preventing replication fork collapse to maintain genome integrity.
Cortez D
(2015) DNA Repair (Amst) 32: 149-157
MeSH Terms: Animals, DNA, DNA Damage, DNA Polymerase III, DNA Repair, DNA Replication, Gene Expression Regulation, Genomic Instability, Humans, Mice, Proliferating Cell Nuclear Antigen, Saccharomyces cerevisiae, Xenopus laevis
Show Abstract · Added February 4, 2016
Billions of base pairs of DNA must be replicated trillions of times in a human lifetime. Complete and accurate replication once and only once per cell division cycle is essential to maintain genome integrity and prevent disease. Impediments to replication fork progression including difficult to replicate DNA sequences, conflicts with transcription, and DNA damage further add to the genome maintenance challenge. These obstacles frequently cause fork stalling, but only rarely cause a failure to complete replication. Robust mechanisms ensure that stalled forks remain stable and capable of either resuming DNA synthesis or being rescued by converging forks. However, when failures do happen the fork collapses leading to genome rearrangements, cell death and disease. Despite intense interest, the mechanisms to repair damaged replication forks, stabilize them, and ensure successful replication remain only partly understood. Different models of fork collapse have been proposed with varying descriptions of what happens to the DNA and replisome. Here, I will define fork collapse and describe what is known about how the replication checkpoint prevents it to maintain genome stability.
Copyright © 2015 Elsevier B.V. All rights reserved.
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13 MeSH Terms