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Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Jiang X, O'Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J, Ingelsson E, Karasik D, Pilz S, Berry D, Kestenbaum B, Zheng J, Luan J, Sofianopoulou E, Streeten EA, Albanes D, Lutsey PL, Yao L, Tang W, Econs MJ, Wallaschofski H, Völzke H, Zhou A, Power C, McCarthy MI, Michos ED, Boerwinkle E, Weinstein SJ, Freedman ND, Huang WY, Van Schoor NM, van der Velde N, Groot LCPGM, Enneman A, Cupples LA, Booth SL, Vasan RS, Liu CT, Zhou Y, Ripatti S, Ohlsson C, Vandenput L, Lorentzon M, Eriksson JG, Shea MK, Houston DK, Kritchevsky SB, Liu Y, Lohman KK, Ferrucci L, Peacock M, Gieger C, Beekman M, Slagboom E, Deelen J, Heemst DV, Kleber ME, März W, de Boer IH, Wood AC, Rotter JI, Rich SS, Robinson-Cohen C, den Heijer M, Jarvelin MR, Cavadino A, Joshi PK, Wilson JF, Hayward C, Lind L, Michaëlsson K, Trompet S, Zillikens MC, Uitterlinden AG, Rivadeneira F, Broer L, Zgaga L, Campbell H, Theodoratou E, Farrington SM, Timofeeva M, Dunlop MG, Valdes AM, Tikkanen E, Lehtimäki T, Lyytikäinen LP, Kähönen M, Raitakari OT, Mikkilä V, Ikram MA, Sattar N, Jukema JW, Wareham NJ, Langenberg C, Forouhi NG, Gundersen TE, Khaw KT, Butterworth AS, Danesh J, Spector T, Wang TJ, Hyppönen E, Kraft P, Kiel DP
(2018) Nat Commun 9: 260
MeSH Terms: Amidohydrolases, Autoimmune Diseases, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D
Show Abstract · Added January 3, 2019
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
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MeSH Terms
Dynamic Glycosylation Governs the Vertebrate COPII Protein Trafficking Pathway.
Cox NJ, Unlu G, Bisnett BJ, Meister TR, Condon BM, Luo PM, Smith TJ, Hanna M, Chhetri A, Soderblom EJ, Audhya A, Knapik EW, Boyce M
(2018) Biochemistry 57: 91-107
MeSH Terms: Acetylglucosamine, Acylation, Animals, COP-Coated Vesicles, Cell Line, Collagen, Craniofacial Abnormalities, Disease Models, Animal, Glycosylation, Humans, Organelles, Protein Conformation, Protein Processing, Post-Translational, Protein Transport, Vertebrates, Vesicular Transport Proteins, Zebrafish
Show Abstract · Added March 15, 2018
The COPII coat complex, which mediates secretory cargo trafficking from the endoplasmic reticulum, is a key control point for subcellular protein targeting. Because misdirected proteins cannot function, protein sorting by COPII is critical for establishing and maintaining normal cell and tissue homeostasis. Indeed, mutations in COPII genes cause a range of human pathologies, including cranio-lenticulo-sutural dysplasia (CLSD), which is characterized by collagen trafficking defects, craniofacial abnormalities, and skeletal dysmorphology. Detailed knowledge of the COPII pathway is required to understand its role in normal cell physiology and to devise new treatments for disorders in which it is disrupted. However, little is known about how vertebrates dynamically regulate COPII activity in response to developmental, metabolic, or pathological cues. Several COPII proteins are modified by O-linked β-N-acetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, but the biochemical and functional effects of these modifications remain unclear. Here, we use a combination of chemical, biochemical, cellular, and genetic approaches to demonstrate that site-specific O-GlcNAcylation of COPII proteins mediates their protein-protein interactions and modulates cargo secretion. In particular, we show that individual O-GlcNAcylation sites of SEC23A, an essential COPII component, are required for its function in human cells and vertebrate development, because mutation of these sites impairs SEC23A-dependent in vivo collagen trafficking and skeletogenesis in a zebrafish model of CLSD. Our results indicate that O-GlcNAc is a conserved and critical regulatory modification in the vertebrate COPII-dependent trafficking pathway.
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17 MeSH Terms
The Par3 polarity protein is an exocyst receptor essential for mammary cell survival.
Ahmed SM, Macara IG
(2017) Nat Commun 8: 14867
MeSH Terms: Animals, Apoptosis, Cadherins, Cell Adhesion Molecules, Cell Line, Cell Polarity, Cell Survival, Enzyme Activation, Epithelial Cells, Female, Gene Knockdown Techniques, Golgi Apparatus, Humans, Lysine, Mammary Glands, Animal, Models, Biological, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphorylation, Protein Domains, Proto-Oncogene Proteins c-akt, Vesicular Transport Proteins, rab GTP-Binding Proteins
Show Abstract · Added April 26, 2017
The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane-protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long-sought exocyst receptor required for targeted membrane-protein delivery.
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23 MeSH Terms
Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum.
Casey AK, Chen S, Novick P, Ferro-Novick S, Wente SR
(2015) Mol Biol Cell 26: 2833-44
MeSH Terms: Animals, Endoplasmic Reticulum, Membrane Proteins, Nuclear Envelope, Nuclear Pore, Nuclear Pore Complex Proteins, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins
Show Abstract · Added February 15, 2016
The nuclear envelope (NE) and endoplasmic reticulum (ER) are components of the same contiguous membrane system and yet have distinct cellular functions. Mounting evidence suggests roles for some ER proteins in the NE for proper nuclear pore complex (NPC) structure and function. In this study, we identify a NE role in Saccharomyces cerevisiae for Lnp1 and Sey1, proteins required for proper cortical ER formation. Both lnp1Δ and sey1Δ mutants exhibit synthetic genetic interactions with mutants in genes encoding key NPC structural components. Both Lnp1 and Sey1 physically associate with other ER components that have established NPC roles, including Rtn1, Yop1, Pom33, and Per33. Of interest, lnp1Δ rtn1Δ mutants but not rtn1Δ sey1Δ mutants exhibit defects in NPC distribution. Furthermore, the essential NPC assembly factor Ndc1 has altered interactions in the absence of Sey1. Lnp1 dimerizes in vitro via its C-terminal zinc finger motif, a property that is required for proper ER structure but not NPC integrity. These findings suggest that Lnp1's role in NPC integrity is separable from functions in the ER and is linked to Ndc1 and Rtn1 interactions.
© 2015 Casey 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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8 MeSH Terms
In vivo cell biology in zebrafish - providing insights into vertebrate development and disease.
Vacaru AM, Unlu G, Spitzner M, Mione M, Knapik EW, Sadler KC
(2014) J Cell Sci 127: 485-95
MeSH Terms: Animals, Cell Biology, Cell Movement, Embryonic Development, Humans, Microtubules, Phenotype, Vertebrates, Vesicular Transport Proteins, Zebrafish
Show Abstract · Added April 26, 2017
Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease.
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10 MeSH Terms
The Scribble polarity protein stabilizes E-cadherin/p120-catenin binding and blocks retrieval of E-cadherin to the Golgi.
Lohia M, Qin Y, Macara IG
(2012) PLoS One 7: e51130
MeSH Terms: Animals, Cadherins, Catenins, Cell Nucleus, Cell Polarity, Endocytosis, Golgi Apparatus, Humans, Lysosomes, Madin Darby Canine Kidney Cells, Membrane Proteins, Models, Biological, Protein Binding, Protein Stability, Protein Transport, Vesicular Transport Proteins
Show Abstract · Added March 20, 2014
Several polarity proteins, including Scribble (Scrb) have been implicated in control of vesicle traffic, and in particular the endocytosis of E-cadherin, but through unknown mechanisms. We now show that depletion of Scrb enhances endocytosis of E-cadherin by weakening the E-cadherin-p120catenin interaction. Unexpectedly, however, the internalized E-cadherin is not degraded but accumulates in the Golgi apparatus. Silencing p120-catenin causes degradation of E-cadherin in lysosomes, but degradation is blocked by the co-depletion of Scrb, which diverts the internalized E-cadherin to the Golgi. Loss of Scrb also enhances E-cadherin binding to retromer components, and retromer is required for Golgi accumulation of Scrb, and E-cadherin stability. These data identify a novel and unanticipated function for Scrb in blocking retromer-mediated diversion of E-cadherin to the Golgi. They provide evidence that polarity proteins can modify the intracellular itinerary for endocytosed membrane proteins.
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16 MeSH Terms
Differential association of postsynaptic signaling protein complexes in striatum and hippocampus.
Baucum AJ, Brown AM, Colbran RJ
(2013) J Neurochem 124: 490-501
MeSH Terms: Animals, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Corpus Striatum, Hippocampus, Immunoprecipitation, Male, Mice, Mice, Inbred C57BL, Microfilament Proteins, Myosins, Nerve Tissue Proteins, Phosphorylation, Protein Phosphatase 1, Receptors, Glutamate, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Subcellular Fractions, Synapses, Vesicular Transport Proteins
Show Abstract · Added June 21, 2013
Distinct physiological stimuli are required for bidirectional synaptic plasticity in striatum and hippocampus, but differences in the underlying signaling mechanisms are poorly understood. We have begun to compare levels and interactions of key excitatory synaptic proteins in whole extracts and subcellular fractions isolated from micro-dissected striatum and hippocampus. Levels of multiple glutamate receptor subunits, calcium/calmodulin-dependent protein kinase II (CaMKII), a highly abundant serine/threonine kinase, and spinophilin, a F-actin and protein phosphatase 1 (PP1) binding protein, were significantly lower in striatal extracts, as well as in synaptic and/or extrasynaptic fractions, compared with similar hippocampal extracts/fractions. However, CaMKII interactions with spinophilin were more robust in striatum compared with hippocampus, and this enhanced association was restricted to the extrasynaptic fraction. NMDAR GluN2B subunits associate with both spinophilin and CaMKII, but spinophilin-GluN2B complexes were enriched in extrasynaptic fractions whereas CaMKII-GluN2B complexes were enriched in synaptic fractions. Notably, the association of GluN2B with both CaMKII and spinophilin was more robust in striatal extrasynaptic fractions compared with hippocampal extrasynaptic fractions. Selective differences in the assembly of synaptic and extrasynaptic signaling complexes may contribute to differential physiological regulation of excitatory transmission in striatum and hippocampus.
© 2012 International Society for Neurochemistry.
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19 MeSH Terms
VAMP-associated protein B (VAPB) promotes breast tumor growth by modulation of Akt activity.
Rao M, Song W, Jiang A, Shyr Y, Lev S, Greenstein D, Brantley-Sieders D, Chen J
(2012) PLoS One 7: e46281
MeSH Terms: Analysis of Variance, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Enzyme Activation, Female, Gene Expression Profiling, Humans, Immunoblotting, Immunohistochemistry, Mice, Microarray Analysis, Oncogene Protein v-akt, Phosphorylation, Plasmids, Spheroids, Cellular, Survival Analysis, Vesicular Transport Proteins
Show Abstract · Added March 5, 2014
VAPB (VAMP- associated protein B) is an ER protein that regulates multiple biological functions. Although aberrant expression of VAPB is associated with breast cancer, its function in tumor cells is poorly understood. In this report, we provide evidence that VAPB regulates breast tumor cell proliferation and AKT activation. VAPB protein expression is elevated in primary and metastatic tumor specimens, and VAPB mRNA expression levels correlated negatively with patient survival in two large breast tumor datasets. Overexpression of VAPB in mammary epithelial cells increased cell growth, whereas VAPB knockdown in tumor cells inhibited cell proliferation in vitro and suppressed tumor growth in orthotopic mammary gland allografts. The growth regulation of mammary tumor cells controlled by VAPB appears to be mediated, at least in part, by modulation of AKT activity. Overexpression of VAPB in MCF10A-HER2 cells enhances phosphorylation of AKT. In contrast, knockdown of VAPB in MMTV-Neu tumor cells inhibited pAKT levels. Pharmacological inhibition of AKT significantly reduced three-dimensional spheroid growth induced by VAPB. Collectively, the genetic, functional and mechanistic analyses suggest a role of VAPB in tumor promotion in human breast cancer.
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19 MeSH Terms
Phosphorylation of Rab11-FIP2 regulates polarity in MDCK cells.
Lapierre LA, Avant KM, Caldwell CM, Oztan A, Apodaca G, Knowles BC, Roland JT, Ducharme NA, Goldenring JR
(2012) Mol Biol Cell 23: 2302-18
MeSH Terms: Adherens Junctions, Animals, Blotting, Western, Cadherins, Catenins, Cell Line, Cell Polarity, Claudins, Dogs, Epithelial Cells, Green Fluorescent Proteins, HEK293 Cells, Humans, Kidney, Membrane Proteins, Microscopy, Confocal, Mutation, Occludin, Phosphorylation, Reverse Transcriptase Polymerase Chain Reaction, Serine, Tight Junctions, Vesicular Transport Proteins
Show Abstract · Added October 7, 2013
The Rab11 effector Rab11-family interacting protein 2 (Rab11-FIP2) regulates transcytosis through its interactions with Rab11a and myosin Vb. Previous studies implicated Rab11-FIP2 in the establishment of polarity in Madin-Darby canine kidney (MDCK) cells through phosphorylation of Ser-227 by MARK2. Here we examine the dynamic role of Rab11-FIP2 phosphorylation on MDCK cell polarity. Endogenous Rab11-FIP2 phosphorylated on Ser-227 coalesces on vesicular plaques during the reestablishment of polarity after either monolayer wounding or calcium switch. Whereas expression of the nonphosphorylatable Rab11-FIP2(S227A) elicits a loss in lumen formation in MDCK cell cysts grown in Matrigel, the putative pseudophosphorylated Rab11-FIP2(S227E) mutant induces the formation of cysts with multiple lumens. On permeable filters, Rab11-FIP2(S227E)-expressing cells exhibit alterations in the composition of both the adherens and tight junctions. At the adherens junction, p120 catenin and K-cadherin are retained, whereas the majority of the E-cadherin is lost. Although ZO-1 is retained at the tight junction, occludin is lost and the claudin composition is altered. Of interest, the effects of Rab11-FIP2 on cellular polarity did not involve myosin Vb or Rab11a. These results indicate that Ser-227 phosphorylation of Rab11-FIP2 regulates the composition of both adherens and tight junctions and is intimately involved in the regulation of polarity in epithelial cells.
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23 MeSH Terms
Traffic jams in fish bones: ER-to-Golgi protein transport during zebrafish development.
Melville DB, Knapik EW
(2011) Cell Adh Migr 5: 114-8
MeSH Terms: Animals, COP-Coated Vesicles, Carrier Proteins, Embryo, Nonmammalian, Endoplasmic Reticulum, Gene Expression Regulation, Developmental, Golgi Apparatus, Humans, Protein Transport, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins, Zebrafish, Zebrafish Proteins
Show Abstract · Added February 19, 2015
Extracellular matrix (ECM) proteins, cell adhesion molecules, cytokines, morphogens and membrane receptors are synthesized in the ER and transported through the Golgi complex to the cell surface and the extracellular space. The first leg in this journey from the ER to Golgi is facilitated by the Coat Protein II (COPII) vesicular carriers. Genetic defects in genes encoding various COPII components cause a broad spectrum of human diseases, from anemia to skeletal deformities. Here, we summarize our findings in zebrafish and discuss how mutations in COPII elements may cause specific cellular and developmental defects.
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13 MeSH Terms