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Glucose Regulates Microtubule Disassembly and the Dose of Insulin Secretion via Tau Phosphorylation.
Ho KH, Yang X, Osipovich AB, Cabrera O, Hayashi ML, Magnuson MA, Gu G, Kaverina I
(2020) Diabetes 69: 1936-1947
MeSH Terms: Animals, Cyclic AMP-Dependent Protein Kinases, Cyclin-Dependent Kinase 5, Glucose, Glycogen Synthase Kinase 3, Insulin Secretion, Insulin-Secreting Cells, Mice, Microtubules, Phosphorylation, Protein Kinase C, tau Proteins
Show Abstract · Added July 2, 2020
The microtubule cytoskeleton of pancreatic islet β-cells regulates glucose-stimulated insulin secretion (GSIS). We have reported that the microtubule-mediated movement of insulin vesicles away from the plasma membrane limits insulin secretion. High glucose-induced remodeling of microtubule network facilitates robust GSIS. This remodeling involves disassembly of old microtubules and nucleation of new microtubules. Here, we examine the mechanisms whereby glucose stimulation decreases microtubule lifetimes in β-cells. Using real-time imaging of photoconverted microtubules, we demonstrate that high levels of glucose induce rapid microtubule disassembly preferentially in the periphery of individual β-cells, and this process is mediated by the phosphorylation of microtubule-associated protein tau. Specifically, high glucose induces tau hyper-phosphorylation via glucose-responsive kinases GSK3, PKA, PKC, and CDK5. This causes dissociation of tau from and subsequent destabilization of microtubules. Consequently, tau knockdown in mouse islet β-cells facilitates microtubule turnover, causing increased basal insulin secretion, depleting insulin vesicles from the cytoplasm, and impairing GSIS. More importantly, tau knockdown uncouples microtubule destabilization from glucose stimulation. These findings suggest that tau suppresses peripheral microtubules turning over to restrict insulin oversecretion in basal conditions and preserve the insulin pool that can be released following stimulation; high glucose promotes tau phosphorylation to enhance microtubule disassembly to acutely enhance GSIS.
© 2020 by the American Diabetes Association.
2 Communities
4 Members
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12 MeSH Terms
DYRK kinase Pom1 drives F-BAR protein Cdc15 from the membrane to promote medial division.
Bhattacharjee R, Mangione MC, Wos M, Chen JS, Snider CE, Roberts-Galbraith RH, McDonald NA, Presti LL, Martin SG, Gould KL
(2020) Mol Biol Cell 31: 917-929
MeSH Terms: Cell Cycle Proteins, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Protein Kinases, Protein Processing, Post-Translational, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 3, 2020
In many organisms, positive and negative signals cooperate to position the division site for cytokinesis. In the rod-shaped fission yeast , symmetric division is achieved through anillin/Mid1-dependent positive cues released from the central nucleus and negative signals from the DYRK-family polarity kinase Pom1 at cell tips. Here we establish that Pom1's kinase activity prevents septation at cell tips even if Mid1 is absent or mislocalized. We also find that Pom1 phosphorylation of F-BAR protein Cdc15, a major scaffold of the division apparatus, disrupts Cdc15's ability to bind membranes and paxillin, Pxl1, thereby inhibiting Cdc15's function in cytokinesis. A Cdc15 mutant carrying phosphomimetic versions of Pom1 sites or deletion of Cdc15 binding partners suppresses division at cell tips in cells lacking both Mid1 and Pom1 signals. Thus, inhibition of Cdc15-scaffolded septum formation at cell poles is a key Pom1 mechanism that ensures medial division.
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9 MeSH Terms
BRAF molecular testing in cytopathology: Implications for diagnosis, prognosis, and targeted therapeutics.
Bergdorf KN, Lee LA, Weiss VL
(2020) Cancer Cytopathol 128: 9-11
MeSH Terms: Antineoplastic Agents, Genetic Testing, Humans, MAP Kinase Signaling System, Molecular Targeted Therapy, Mutation, Neoplasms, Phosphorylation, Precision Medicine, Prognosis, Proto-Oncogene Proteins B-raf
Added March 3, 2020
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1 Members
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11 MeSH Terms
Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.
Watanabe M, Zhang J, Mansuri MS, Duan J, Karimy JK, Delpire E, Alper SL, Lifton RP, Fukuda A, Kahle KT
(2019) Sci Signal 12:
MeSH Terms: Animals, Animals, Newborn, Binding Sites, Cells, Cultured, Central Nervous System, Chlorides, Gene Expression Regulation, Developmental, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Neurons, Phosphorylation, Signal Transduction, Symporters, gamma-Aminobutyric Acid
Show Abstract · Added March 18, 2020
Despite its importance for γ-aminobutyric acid (GABA) inhibition and involvement in neurodevelopmental disease, the regulatory mechanisms of the K/Cl cotransporter KCC2 (encoded by ) during maturation of the central nervous system (CNS) are not entirely understood. Here, we applied quantitative phosphoproteomics to systematically map sites of KCC2 phosphorylation during CNS development in the mouse. KCC2 phosphorylation at Thr and Thr, which inhibits KCC2 activity, underwent dephosphorylation in parallel with the GABA excitatory-inhibitory sequence in vivo. Knockin mice expressing the homozygous phosphomimetic KCC2 mutations T906E/T1007E ( ), which prevented the normal developmentally regulated dephosphorylation of these sites, exhibited early postnatal death from respiratory arrest and a marked absence of cervical spinal neuron respiratory discharges. mice also displayed disrupted lumbar spinal neuron locomotor rhythmogenesis and touch-evoked status epilepticus associated with markedly impaired KCC2-dependent Cl extrusion. These data identify a previously unknown phosphorylation-dependent KCC2 regulatory mechanism during CNS development that is essential for dynamic GABA-mediated inhibition and survival.
Copyright © 2019 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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1 Members
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16 MeSH Terms
Interaction of α Carboxyl Terminus 1 Peptide With the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia-Reperfusion Injury.
Jiang J, Hoagland D, Palatinus JA, He H, Iyyathurai J, Jourdan LJ, Bultynck G, Wang Z, Zhang Z, Schey K, Poelzing S, McGowan FX, Gourdie RG
(2019) J Am Heart Assoc 8: e012385
MeSH Terms: Animals, Computer Simulation, Connexin 43, Mice, Microscopy, Confocal, Myocardial Contraction, Myocardial Reperfusion Injury, Peptide Fragments, Phosphorylation, Surface Plasmon Resonance, Tandem Mass Spectrometry, Ventricular Function, Left, Zonula Occludens-1 Protein
Show Abstract · Added March 24, 2020
Background α Carboxyl terminus 1 (αCT1) is a 25-amino acid therapeutic peptide incorporating the zonula occludens-1 (ZO-1)-binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that αCT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase Cε phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of αCT1 in mitigating cardiac ischemia-reperfusion injury. Methods and Results To study αCT1-mediated increases in phosphorylation of Cx43 at serine 368, we undertook mass spectrometry of protein kinase Cε phosphorylation assay reactants. This indicated potential interaction between negatively charged residues in the αCT1 Asp-Asp-Leu-Glu-Iso sequence and lysines (Lys345, Lys346) in an α-helical sequence (helix 2) within the Cx43-CT. In silico modeling provided further support for this interaction, indicating that αCT1 may interact with both Cx43 and ZO-1. Using surface plasmon resonance, thermal shift, and phosphorylation assays, we characterized a series of αCT1 variants, identifying peptides that interacted with either ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 or Cx43-CT, but with limited or no ability to bind both molecules. Only peptides competent to interact with Cx43-CT, but not ZO-1-postsynaptic density-95/disks large/zonula occludens-1 2 alone, prompted increased pS368 phosphorylation. Moreover, in an ex vivo mouse model of ischemia-reperfusion injury, preischemic infusion only with those peptides competent to bind Cx43 preserved ventricular function after ischemia-reperfusion. Interestingly, a short 9-amino acid variant of αCT1 (αCT11) demonstrated potent cardioprotective effects when infused either before or after ischemic injury. Conclusions Interaction of αCT1 with the Cx43, but not ZO-1, is correlated with cardioprotection. Pharmacophores targeting Cx43-CT could provide a translational approach to preserving heart function after ischemic injury.
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13 MeSH Terms
Normal Saline solutions cause endothelial dysfunction through loss of membrane integrity, ATP release, and inflammatory responses mediated by P2X7R/p38 MAPK/MK2 signaling pathways.
Cheung-Flynn J, Alvis BD, Hocking KM, Guth CM, Luo W, McCallister R, Chadalavada K, Polcz M, Komalavilas P, Brophy CM
(2019) PLoS One 14: e0220893
MeSH Terms: Adenosine Triphosphate, Animals, Aorta, Cell Membrane, Endothelial Cells, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Receptors, Purinergic P2X7, Saline Solution, Saphenous Vein, Signal Transduction, Swine, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 3, 2020
Resuscitation with 0.9% Normal Saline (NS), a non-buffered acidic solution, leads to increased morbidity and mortality in the critically ill. The goal of this study was to determine the molecular mechanisms of endothelial injury after exposure to NS. The hypothesis of this investigation is that exposure of endothelium to NS would lead to loss of cell membrane integrity, resulting in release of ATP, activation of the purinergic receptor (P2X7R), and subsequent activation of stress activated signaling pathways and inflammation. Human saphenous vein endothelial cells (HSVEC) incubated in NS, but not buffered electrolyte solution (Plasma-Lyte, PL), exhibited abnormal morphology and increased release of lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and decreased transendothelial resistance (TEER), suggesting loss of membrane integrity. Incubation of intact rat aorta (RA) or human saphenous vein in NS but not PL led to impaired endothelial-dependent relaxation which was ameliorated by apyrase (hydrolyzes ATP) or SB203580 (p38 MAPK inhibitor). Exposure of HSVEC to NS but not PL led to activation of p38 MAPK and its downstream substrate, MAPKAP kinase 2 (MK2). Treatment of HSVEC with exogenous ATP led to interleukin 1β (IL-1β) release and increased vascular cell adhesion molecule (VCAM) expression. Treatment of RA with IL-1β led to impaired endothelial relaxation. IL-1β treatment of HSVEC led to increases in p38 MAPK and MK2 phosphorylation, and increased levels of arginase II. Incubation of porcine saphenous vein (PSV) in PL with pH adjusted to 6.0 or less also led to impaired endothelial function, suggesting that the acidic nature of NS is what contributes to endothelial dysfunction. Volume overload resuscitation in a porcine model after hemorrhage with NS, but not PL, led to acidosis and impaired endothelial function. These data suggest that endothelial dysfunction caused by exposure to acidic, non-buffered NS is associated with loss of membrane integrity, release of ATP, and is modulated by P2X7R-mediated inflammatory responses.
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17 MeSH Terms
Widespread Tau-Specific CD4 T Cell Reactivity in the General Population.
Lindestam Arlehamn CS, Pham J, Alcalay RN, Frazier A, Shorr E, Carpenter C, Sidney J, Dhanwani R, Agin-Liebes J, Garretti F, Amara AW, Standaert DG, Phillips EJ, Mallal SA, Peters B, Sulzer D, Sette A
(2019) J Immunol 203: 84-92
MeSH Terms: Adult, Aged, Aged, 80 and over, Autoimmunity, CD4-Positive T-Lymphocytes, Cells, Cultured, Clonal Selection, Antigen-Mediated, Female, Humans, Immune Tolerance, Male, Middle Aged, Peptides, Phosphorylation, Protein Aggregation, Pathological, T-Cell Antigen Receptor Specificity, Young Adult, tau Proteins
Show Abstract · Added March 30, 2020
Tau protein is found to be aggregated and hyperphosphorylated (p-tau) in many neurologic disorders, including Parkinson disease (PD) and related parkinsonisms, Alzheimer disease, traumatic brain injury, and even in normal aging. Although not known to produce autoimmune responses, we hypothesized that the appearance of aggregated tau and p-tau with disease could activate the immune system. We thus compared T cell responses to tau and p-tau-derived peptides between PD patients, age-matched healthy controls, and young healthy controls (<35 y old; who are less likely to have high levels of tau aggregates). All groups exhibited CD4 T cell responses to tau-derived peptides, which were associated with secretion of IFN-γ, IL-5, and/or IL-4. The PD and control participants exhibited a similar magnitude and breadth of responses. Some tau-derived epitopes, consisting of both unmodified and p-tau residues, were more highly represented in PD participants. These results were verified in an independent set of PD and control donors (either age-matched or young controls). Thus, T cells recognizing tau epitopes escape central and peripheral tolerance in relatively high numbers, and the magnitude and nature of these responses are not modulated by age or PD disease.
Copyright © 2019 by The American Association of Immunologists, Inc.
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1 Members
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MeSH Terms
A Novel Class of Common Docking Domain Inhibitors That Prevent ERK2 Activation and Substrate Phosphorylation.
Sammons RM, Perry NA, Li Y, Cho EJ, Piserchio A, Zamora-Olivares DP, Ghose R, Kaoud TS, Debevec G, Bartholomeusz C, Gurevich VV, Iverson TM, Giulianotti M, Houghten RA, Dalby KN
(2019) ACS Chem Biol 14: 1183-1194
MeSH Terms: Binding Sites, Crystallography, X-Ray, Dose-Response Relationship, Drug, Enzyme Activation, Guanidine, Humans, Mitogen-Activated Protein Kinase 1, Nuclear Magnetic Resonance, Biomolecular, Phosphorylation, Protein Kinase Inhibitors, Substrate Specificity
Show Abstract · Added March 18, 2020
Extracellular signal-regulated kinases (ERK1/2) are mitogen-activated protein kinases (MAPKs) that play a pro-tumorigenic role in numerous cancers. ERK1/2 possess two protein-docking sites that are distinct from the active site: the D-recruitment site (DRS) and the F-recruitment site. These docking sites facilitate substrate recognition, intracellular localization, signaling specificity, and protein complex assembly. Targeting these sites on ERK in a therapeutic context may overcome many problems associated with traditional ATP-competitive inhibitors. Here, we identified a new class of inhibitors that target the ERK DRS by screening a synthetic combinatorial library of more than 30 million compounds. The screen detects the competitive displacement of a fluorescent peptide from the DRS of ERK2. The top molecular scaffold from the screen was optimized for structure-activity relationship by positional scanning of different functional groups. This resulted in 10 compounds with similar binding affinities and a shared core structure consisting of a tertiary amine hub with three functionalized cyclic guanidino branches. Compound 2507-1 inhibited ERK2 from phosphorylating a DRS-targeting substrate and prevented the phosphorylation of ERK2 by a constitutively active MEK1 (MAPK/ERK kinase 1) mutant. Interaction between an analogue, 2507-8, and the ERK2 DRS was confirmed by nuclear magnetic resonance and X-ray crystallography. 2507-8 forms critical interactions at the common docking domain residue Asp319 via an arginine-like moiety that is shared by all 10 hits, suggesting a common binding mode. The structural and biochemical insights reported here provide the basis for developing new ERK inhibitors that are not ATP-competitive but instead function by disrupting critical protein-protein interactions.
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MeSH Terms
Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner.
Gowrikumar S, Ahmad R, Uppada SB, Washington MK, Shi C, Singh AB, Dhawan P
(2019) Oncogene 38: 5321-5337
MeSH Terms: Animals, Biomarkers, Tumor, Cells, Cultured, Claudin-1, Colitis, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Inflammatory Bowel Diseases, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Prognosis, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Receptors, Notch, Signal Transduction, Up-Regulation, beta Catenin
Show Abstract · Added April 24, 2019
In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1 (Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound-healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice are used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and the underlying mechanism was determined using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation and defective epithelial homeostasis accompanied the increased CAC in Villin-Cld-1-Tg mice. We further found significantly increased levels of protumorigenic M2 macrophages and β-cateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg vs. WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1-dependent activation of the β-CatSer552, which, in turn, was dependent on proinflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its noncanonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.
1 Communities
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22 MeSH Terms
NDR Kinase Sid2 Drives Anillin-like Mid1 from the Membrane to Promote Cytokinesis and Medial Division Site Placement.
Willet AH, DeWitt AK, Beckley JR, Clifford DM, Gould KL
(2019) Curr Biol 29: 1055-1063.e2
MeSH Terms: Actin Cytoskeleton, Cell Cycle Checkpoints, Cytokinesis, Mitosis, Phosphorylation, Protein Kinases, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Signal Transduction
Show Abstract · Added April 10, 2019
In animals and fungi, cytokinesis is facilitated by the constriction of an actomyosin contractile ring (CR) [1]. In Schizosaccharomyces pombe, the CR forms mid-cell during mitosis from clusters of proteins at the medial cell cortex called nodes [2]. The anillin-like protein Mid1 localizes to nodes and is required for CR assembly at mid-cell [3]. When CR constriction begins, Mid1 leaves the division site. How Mid1 disassociates and whether this step is important for cytokinetic progression has been unknown. The septation initiation network (SIN), analogous to the Hippo pathway of multicellular organisms, is a signaling cascade that triggers node dispersal, CR assembly and constriction, and septum formation [4, 5]. We report that the terminal SIN kinase, Sid2 [6], phosphorylates Mid1 to drive its removal from the cortex at CR constriction onset. A Mid1 mutant that cannot be phosphorylated by Sid2 remains cortical during cytokinesis, over-accumulates in interphase nodes following cell division in a manner dependent on the SAD kinase Cdr2, advances the G2/M transition, precociously recruits other CR components to nodes, pulls Cdr2 aberrantly into the CR, and reduces rates of CR maturation and constriction. When combined with cdr2 mutants that affect node assembly or disassembly, gross defects in division site positioning result. Our findings identify Mid1 as a key Sid2 substrate for SIN-mediated remodeling of the division site for efficient cytokinesis and provide evidence that nodes serve to integrate signals coordinating cell cycle progression and cytokinesis.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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9 MeSH Terms