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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
3 Members
0 Resources
12 MeSH Terms
Regulation of Glucose-Dependent Golgi-Derived Microtubules by cAMP/EPAC2 Promotes Secretory Vesicle Biogenesis in Pancreatic β Cells.
Trogden KP, Zhu X, Lee JS, Wright CVE, Gu G, Kaverina I
(2019) Curr Biol 29: 2339-2350.e5
MeSH Terms: Animals, Cyclic AMP, Glucose, Golgi Apparatus, Guanine Nucleotide Exchange Factors, Insulin-Secreting Cells, Male, Mice, Mice, Inbred ICR, Microtubules, Organelle Biogenesis, Secretory Vesicles
Show Abstract · Added August 6, 2019
The microtubule (MT) network is an essential regulator of insulin secretion from pancreatic β cells, which is central to blood-sugar homeostasis. We find that when glucose metabolism induces insulin secretion, it also increases formation of Golgi-derived microtubules (GDMTs), notably with the same biphasic kinetics as insulin exocytosis. Furthermore, GDMT nucleation is controlled by a glucose signal-transduction pathway through cAMP and its effector EPAC2. Preventing new GDMT nucleation dramatically affects the pipeline of insulin production, storage, and release. There is an overall reduction of β-cell insulin content, and remaining insulin becomes retained within the Golgi, likely because of stalling of insulin-granule budding. While not preventing glucose-induced insulin exocytosis, the diminished granule availability substantially blunts the amount secreted. Constant dynamic maintenance of the GDMT network is therefore critical for normal β-cell physiology. Our study demonstrates that the biogenesis of post-Golgi carriers, particularly large secretory granules, requires ongoing nucleation and replenishment of the GDMT network.
Copyright © 2019 Elsevier Ltd. All rights reserved.
2 Communities
2 Members
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12 MeSH Terms
p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton.
Fuertes-Alvarez S, Maeso-Alonso L, Villoch-Fernandez J, Wildung M, Martin-Lopez M, Marshall C, Villena-Cortes AJ, Diez-Prieto I, Pietenpol JA, Tissir F, Lizé M, Marques MM, Marin MC
(2018) Cell Death Dis 9: 1183
MeSH Terms: Animals, Carrier Proteins, Cell Polarity, Cilia, Cytoskeleton, Ependyma, Female, Frizzled Receptors, Gene Expression Regulation, Gene Ontology, HCT116 Cells, Humans, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Microtubules, Molecular Sequence Annotation, Nerve Tissue Proteins, Nonmuscle Myosin Type IIA, Pluripotent Stem Cells, Signal Transduction, Tumor Protein p73
Show Abstract · Added March 27, 2019
Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton.
0 Communities
1 Members
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24 MeSH Terms
The balance between adhesion and contraction during cell division.
Taneja N, Rathbun L, Hehnly H, Burnette DT
(2019) Curr Opin Cell Biol 56: 45-52
MeSH Terms: Animals, Cell Adhesion, Centrosome, Humans, Microtubules, Mitosis, Signal Transduction, Spindle Apparatus
Show Abstract · Added March 27, 2019
The ability to divide is a fundamental property of a living cell. The 3D orientation of cell division is essential for embryogenesis, maintenance of tissue organization and architecture, as well as controlling cell fate. Much attention has been placed on the mitotic spindle's role in placing itself along the cell's longest axis, where a shape sensing mechanism between a population of microtubules extending from mitotic centrosomes to the cell cortex occurs. However, contractile forces at the cell cortex also likely play a decisive role in determining the final placement of daughter cells following division. In this review, we discuss recent literature that describes the role of these contractile forces and how these forces could be balanced by mitotic adhesion complexes.
Copyright © 2018 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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8 MeSH Terms
Microtubule minus-end aster organization is driven by processive HSET-tubulin clusters.
Norris SR, Jung S, Singh P, Strothman CE, Erwin AL, Ohi MD, Zanic M, Ohi R
(2018) Nat Commun 9: 2659
MeSH Terms: Animals, Cell Tracking, Green Fluorescent Proteins, HeLa Cells, Humans, Kinesin, Microscopy, Fluorescence, Microtubules, Molecular Motor Proteins, Protein Binding, Time-Lapse Imaging, Tubulin
Show Abstract · Added March 3, 2020
Higher-order structures of the microtubule (MT) cytoskeleton are comprised of two architectures: bundles and asters. Although both architectures are critical for cellular function, the molecular pathways that drive aster formation are poorly understood. Here, we study aster formation by human minus-end-directed kinesin-14 (HSET/KIFC1). We show that HSET is incapable of forming asters from preformed, nongrowing MTs, but rapidly forms MT asters in the presence of soluble (non-MT) tubulin. HSET binds soluble (non-MT) tubulin via its N-terminal tail domain to form heterogeneous HSET-tubulin clusters containing multiple motors. Cluster formation induces motor processivity and rescues the formation of asters from nongrowing MTs. We then show that excess soluble (non-MT) tubulin stimulates aster formation in HeLa cells overexpressing HSET during mitosis. We propose a model where HSET can toggle between MT bundle and aster formation in a manner governed by the availability of soluble (non-MT) tubulin.
0 Communities
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MeSH Terms
Loss of CENP-F Results in Dilated Cardiomyopathy with Severe Disruption of Cardiac Myocyte Architecture.
Manalo A, Schroer AK, Fenix AM, Shancer Z, Coogan J, Brolsma T, Burnette DT, Merryman WD, Bader DM
(2018) Sci Rep 8: 7546
MeSH Terms: Animals, Cardiomyopathy, Dilated, Chromosomal Proteins, Non-Histone, Disease Models, Animal, Genetic Association Studies, Genetic Predisposition to Disease, Heart Failure, Humans, Intercellular Junctions, Loss of Function Mutation, Mice, Microfilament Proteins, Microtubules, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Stroke Volume
Show Abstract · Added March 27, 2019
Centromere-binding protein F (CENP-F) is a very large and complex protein with many and varied binding partners including components of the microtubule network. Numerous CENP-F functions impacting diverse cellular behaviors have been identified. Importantly, emerging data have shown that CENP-F loss- or gain-of-function has critical effects on human development and disease. Still, it must be noted that data at the single cardiac myocyte level examining the impact of CENP-F loss-of-function on fundamental cellular behavior is missing. To address this gap in our knowledge, we analyzed basic cell structure and function in cardiac myocytes devoid of CENP-F. We found many diverse structural abnormalities including disruption of the microtubule network impacting critical characteristics of the cardiac myocyte. This is the first report linking microtubule network malfunction to cardiomyopathy. Importantly, we also present data demonstrating a direct link between a CENP-F single nucleotide polymorphism (snp) and human cardiac disease. In a proximate sense, these data examining CENP-F function explain the cellular basis underlying heart disease in this genetic model and, in a larger sense, they will hopefully provide a platform upon which the field can explore diverse cellular outcomes in wide-ranging areas of research on this critical protein.
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1 Members
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16 MeSH Terms
Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma.
Chiang YC, Park IY, Terzo EA, Tripathi DN, Mason FM, Fahey CC, Karki M, Shuster CB, Sohn BH, Chowdhury P, Powell RT, Ohi R, Tsai YS, de Cubas AA, Khan A, Davis IJ, Strahl BD, Parker JS, Dere R, Walker CL, Rathmell WK
(2018) Cancer Res 78: 3135-3146
MeSH Terms: Animals, Carcinogenesis, Carcinoma, Renal Cell, Cell Line, Tumor, Chromosomes, Human, Pair 3, Fibroblasts, Gene Knockdown Techniques, Genomic Instability, Haploinsufficiency, Histone-Lysine N-Methyltransferase, Histones, Humans, Kidney Neoplasms, Kidney Tubules, Proximal, Lysine, Methylation, Mice, Micronuclei, Chromosome-Defective, Microtubules
Show Abstract · Added October 30, 2019
Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase , which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic, -deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In -inactivated human kidney cells, rescue with a pathogenic mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis. .
©2018 American Association for Cancer Research.
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MeSH Terms
Microtubules regulate brush border formation.
Tonucci FM, Ferretti A, Almada E, Cribb P, Vena R, Hidalgo F, Favre C, Tyska MJ, Kaverina I, Larocca MC
(2018) J Cell Physiol 233: 1468-1480
MeSH Terms: Actin Cytoskeleton, Animals, Cell Polarity, Centromere, Colon, Dogs, Enterocytes, Epithelial Cells, Humans, Kidney, Madin Darby Canine Kidney Cells, Microtubule-Associated Proteins, Microtubules, Microvilli, Nocodazole, Time Factors, Tubulin Modulators
Show Abstract · Added April 10, 2018
Most epithelial cells contain apical membrane structures associated to bundles of actin filaments, which constitute the brush border. Whereas microtubule participation in the maintenance of the brush border identity has been characterized, their contribution to de novo microvilli organization remained elusive. Hereby, using a cell model of individual enterocyte polarization, we found that nocodazole induced microtubule depolymerization prevented the de novo brush border formation. Microtubule participation in brush border actin organization was confirmed in polarized kidney tubule MDCK cells. We also found that centrosome, but not Golgi derived microtubules, were essential for the initial stages of brush border development. During this process, microtubule plus ends acquired an early asymmetric orientation toward the apical membrane, which clearly differs from their predominant basal orientation in mature epithelia. In addition, overexpression of the microtubule plus ends associated protein CLIP170, which regulate actin nucleation in different cell contexts, facilitated brush border formation. In combination, the present results support the participation of centrosomal microtubule plus ends in the activation of the polarized actin organization associated to brush border formation, unveiling a novel mechanism of microtubule regulation of epithelial polarity.
© 2017 Wiley Periodicals, Inc.
0 Communities
1 Members
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MeSH Terms
Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity.
Chen GY, Kang YJ, Gayek AS, Youyen W, Tüzel E, Ohi R, Hancock WO
(2017) ACS Chem Biol 12: 1038-1046
MeSH Terms: Animals, Cell Line, Humans, Kinesin, Metaphase, Microtubules, Spindle Apparatus
Show Abstract · Added April 18, 2017
To uncover their contrasting mechanisms, antimitotic drugs that inhibit Eg5 (kinesin-5) were analyzed in mixed-motor gliding assays of kinesin-1 and Eg5 motors in which Eg5 "braking" dominates motility. Loop-5 inhibitors (monastrol, STLC, ispinesib, and filanesib) increased gliding speeds, consistent with inducing a weak-binding state in Eg5, whereas BRD9876 slowed gliding, consistent with locking Eg5 in a rigor state. Biochemical and single-molecule assays demonstrated that BRD9876 acts as an ATP- and ADP-competitive inhibitor with 4 nM K. Consistent with its microtubule polymerase activity, Eg5 was shown to stabilize microtubules against depolymerization. This stabilization activity was eliminated in monastrol but was enhanced by BRD9876. Finally, in metaphase-arrested RPE-1 cells, STLC promoted spindle collapse, whereas BRD9876 did not. Thus, different Eg5 inhibitors impact spindle assembly and architecture through contrasting mechanisms, and rigor inhibitors may paradoxically have the capacity to stabilize microtubule arrays in cells.
0 Communities
1 Members
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7 MeSH Terms
Methylated α-tubulin antibodies recognize a new microtubule modification on mitotic microtubules.
Park IY, Chowdhury P, Tripathi DN, Powell RT, Dere R, Terzo EA, Rathmell WK, Walker CL
(2016) MAbs 8: 1590-1597
MeSH Terms: Antibodies, Antibodies, Monoclonal, Humans, Lysine, Methylation, Microtubules, Mitosis, Protein Processing, Post-Translational, Tubulin
Show Abstract · Added October 30, 2019
Posttranslational modifications (PTMs) on microtubules differentiate these cytoskeletal elements for a variety of cellular functions. We recently identified SETD2 as a dual-function histone and microtubule methyltransferase, and methylation as a new microtubule PTM that occurs on lysine 40 of α-tubulin, which is trimethylated (α-TubK40me3) by SETD2. In the course of these studies, we generated polyclonal (α-TubK40me3 pAb) and monoclonal (α-TubK40me3 mAb) antibodies to a methylated α-tubulin peptide (GQMPSD-Kme3-TIGGGDC). Here, we characterize these antibodies, and the specific mono-, di- or tri-methylated lysine residues they recognize. While both the pAb and mAb antibodies recognized lysines methylated by SETD2 on microtubules and histones, the clone 18 mAb was more specific for methylated microtubules, with little cross-reactivity for methylated histones. The clone 18 mAb recognized specific subsets of microtubules during mitosis and cytokinesis, and lacked the chromatin staining seen by immunocytochemistry with the pAb. Western blot analysis using these antibodies revealed that methylated α-tubulin migrated faster than unmethylated α-tubulin, suggesting methylation may be a signal for additional processing of α-tubulin and/or microtubules. As the first reagents that specifically recognize methylated α-tubulin, these antibodies are a valuable tool for studying this new modification of the cytoskeleton, and the function of methylated microtubules.
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MeSH Terms