Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation
Publication Date
May 01, 2012
Journal
PLOS Biology
Authors
Tomas Garzon Muvdi, Paula Schiapparelli, Colette Ap Rhys, Hugo Guerrero Cazares, et al
Volume
10
Issue
5
Pages
e1001320
DOI
https://dx.plos.org/10.1371/journal.pbio.1001320
Publisher URL
http://journals.plos.org/plosbiology/article?id=10.1371%2Fjournal.pbio.1001320
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22570591
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341330
Europe PMC
http://europepmc.org/abstract/MED/22570591
Web of Science
000304770600004
Scopus
84861569709
Mendeley
http://www.mendeley.com/research/regulation-brain-tumor-dispersal-nkcc1-through-novel-role-focal-adhesion-regulation
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Mendeley | Further Information

{"title"=>"Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation", "type"=>"journal", "authors"=>[{"first_name"=>"Tomas", "last_name"=>"Garzon-Muvdi", "scopus_author_id"=>"56013525900"}, {"first_name"=>"Paula", "last_name"=>"Schiapparelli", "scopus_author_id"=>"36022035200"}, {"first_name"=>"Colette", "last_name"=>"ap Rhys", "scopus_author_id"=>"6505817748"}, {"first_name"=>"Hugo", "last_name"=>"Guerrero-Cazares", "scopus_author_id"=>"15848345600"}, {"first_name"=>"Christopher", "last_name"=>"Smith", "scopus_author_id"=>"57200445695"}, {"first_name"=>"Deok Ho", "last_name"=>"Kim", "scopus_author_id"=>"36016798200"}, {"first_name"=>"Lyonell", "last_name"=>"Kone", "scopus_author_id"=>"55232802100"}, {"first_name"=>"Harrison", "last_name"=>"Farber", "scopus_author_id"=>"7005716132"}, {"first_name"=>"Danielle Y.", "last_name"=>"Lee", "scopus_author_id"=>"57199466881"}, {"first_name"=>"Steven S.", "last_name"=>"An", "scopus_author_id"=>"7203025184"}, {"first_name"=>"Andre", "last_name"=>"Levchenko", "scopus_author_id"=>"55789505518"}, {"first_name"=>"Alfredo", "last_name"=>"Quiñones-Hinojosa", "scopus_author_id"=>"7004875939"}], "year"=>2012, "source"=>"PLoS Biology", "identifiers"=>{"sgr"=>"84861569709", "doi"=>"10.1371/journal.pbio.1001320", "pui"=>"364901032", "issn"=>"15449173", "pmid"=>"22570591", "isbn"=>"1545-7885 (Electronic)\\n1544-9173 (Linking)", "scopus"=>"2-s2.0-84861569709"}, "id"=>"20d86dfb-c5d7-3ed5-b52d-355331f14292", "abstract"=>"Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.", "link"=>"http://www.mendeley.com/research/regulation-brain-tumor-dispersal-nkcc1-through-novel-role-focal-adhesion-regulation", "reader_count"=>62, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>7, "Researcher"=>12, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>7, "Researcher"=>12, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>5, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>4, "Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>27, "Medicine and Dentistry"=>10, "Neuroscience"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>2, "Chemistry"=>2, "Social Sciences"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>4}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>10}, "Neuroscience"=>{"Neuroscience"=>6}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>27}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Republic of Singapore"=>1, "Canada"=>1, "United States"=>1, "United Kingdom"=>1, "Mexico"=>1}, "group_count"=>4}

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/643695"], "description"=>"<p>Quantification of transwell invasion assays of primary-cultured GB cells exposed to increasing doses of the NKCC1 inhibitor bumetanide (A) or transduced with NKCC1 shRNA (B); exposed to 10 µM of the KCC inhibitor DIOA (C) or stably transduced with KCC4 shRNA (D). Insets show schematic representation of the experimental design in (A) and (D). (E–F) Orhtotopic in vivo tumors formed by NKCC1shRNA cells were significantly larger and less invasive than control cells. Inset shows NKCC1 knockdown by protein expression. (G) Representative images of DAPI-stained coronal sections of mouse brains, after the implantation of control shRNA (left panel) or NKCC1 shRNA (right panel) cells. (G′) Confocal images of human-specific Nestin positive cells migrating across the corpus callosum at the area in the dotted square in (G). These results suggest that NKCC1 expression is necessary for efficient GB cell migration in vivo. Scale bars, 500 µm in low magnification panels and 20 µm in high confocal images panels. Bars represent mean ± SEM. * <i>p</i> value<0.05; ** <i>p</i><0.005.</p>", "links"=>[], "tags"=>["gb", "vitro", "inhibition", "leads", "invasive", "tumors"], "article_id"=>314176, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_activity_is_necessary_for_GB_cell_invasion_in_vitro_and_its_inhibition_leads_to_formation_of_less_invasive_tumors_in_vivo_/314176", "title"=>"NKCC1 activity is necessary for GB cell invasion in vitro and its inhibition leads to formation of less invasive tumors in vivo.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:09:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/644327"], "description"=>"<p>(A) Images of NS 253 cells immunostained with T4 antibody (red, left panel), WNK3 antibody (green, center panel), and DAPI (blue). The right panel shows co-localization of NKCC1 and WNK3 immunoreactivity. Below, high magnification images of the area in the dotted boxes are presented for more detail. Areas of colocalization are pointed out using arrowheads. Scale bars represent 50 µm. (B) Images of NS 561 cells expressing NKCC1-GFP protein migrating on a nanopatterned substrate shows localization to the advancing edge of extending processes in migrating cells at time-point 0 min (left panel), 2 h (center left panel), 3 h (center right panel), and 4 h (right panel).</p>", "links"=>[], "tags"=>["localizes", "extending", "processes", "migrating", "cells", "directional"], "article_id"=>314797, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_localizes_to_the_extending_processes_of_migrating_cells_with_directional_polarization_/314797", "title"=>"NKCC1 localizes to the extending processes of migrating cells with directional polarization.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:19:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/643793"], "description"=>"<p>(A) Quantification of NKCC1 immunoreactivity in a tissue microarray (TMA) containing samples of multiple glial tumors of different grades. The quantification was done using FRIDA software <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001320#pbio.1001320-Halushka1\" target=\"_blank\">[100]</a>. Red lines represent mean immunoreactivity levels. (B) Representative images of NKCC1 immunohistochemistry in tissue cores from the TMA including glial tumors of different grades, normal brain, and epithelial tissues, which express NKCC1 in the apical surface of epithelial cells as a positive control. (C) Immunoblot showing NKCC1 expression in multiple glioma cell lines. Information on the number of samples, age, and gender of the patient of origin of each tumor type can be found in Tables S1 and S2. (D) KCC4 expression by real-time PCR in different glioma cell lines. * <i>p</i> value<0.001.</p>", "links"=>[], "tags"=>["gb", "samples"], "article_id"=>314274, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g002", "stats"=>{"downloads"=>1, "page_views"=>68, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_is_highly_expressed_in_GB_tissue_samples_and_primary_human_GB_cells_/314274", "title"=>"NKCC1 is highly expressed in GB tissue samples and primary human GB cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:11:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/643865"], "description"=>"<p>Quantification of migration speed (A–B) and directionality (C–D) of two different GB cell lines stably transduced with NKCC1 shRNA. NKCC1 shRNA-transduced cells show a decreased migration speed and directionality when compared to control virus-transduced cells. Bars represent mean ± S.E.M. * <i>p</i> value<0.05; ** <i>p</i> value<0.001. Scale bar represents 50 µm.</p>", "links"=>[], "tags"=>["gb", "nanopatterned"], "article_id"=>314352, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g003", "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_activity_is_necessary_for_GB_cell_migration_on_a_nanopatterned_substrate_/314352", "title"=>"NKCC1 activity is necessary for GB cell migration on a nanopatterned substrate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:12:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/333328", "https://ndownloader.figshare.com/files/333365", "https://ndownloader.figshare.com/files/333414", "https://ndownloader.figshare.com/files/333470", "https://ndownloader.figshare.com/files/333523", "https://ndownloader.figshare.com/files/333571", "https://ndownloader.figshare.com/files/333642", "https://ndownloader.figshare.com/files/333685", "https://ndownloader.figshare.com/files/333730", "https://ndownloader.figshare.com/files/333768", "https://ndownloader.figshare.com/files/333916", "https://ndownloader.figshare.com/files/333982", "https://ndownloader.figshare.com/files/334032"], "description"=>"<div><p>Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na<sup>+</sup>-K<sup>+</sup>-Cl<sup>−</sup> cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.</p> </div>", "links"=>[], "tags"=>["dispersal", "nkcc1", "focal", "adhesion"], "article_id"=>125826, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>["https://dx.doi.org/10.1371/journal.pbio.1001320.s001", "https://dx.doi.org/10.1371/journal.pbio.1001320.s002", "https://dx.doi.org/10.1371/journal.pbio.1001320.s003", "https://dx.doi.org/10.1371/journal.pbio.1001320.s004", "https://dx.doi.org/10.1371/journal.pbio.1001320.s005", "https://dx.doi.org/10.1371/journal.pbio.1001320.s006", "https://dx.doi.org/10.1371/journal.pbio.1001320.s007", "https://dx.doi.org/10.1371/journal.pbio.1001320.s008", "https://dx.doi.org/10.1371/journal.pbio.1001320.s009", "https://dx.doi.org/10.1371/journal.pbio.1001320.s010", "https://dx.doi.org/10.1371/journal.pbio.1001320.s011", "https://dx.doi.org/10.1371/journal.pbio.1001320.s012", "https://dx.doi.org/10.1371/journal.pbio.1001320.s013"], "stats"=>{"downloads"=>16, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Regulation_of_Brain_Tumor_Dispersal_by_NKCC1_Through_a_Novel_Role_in_Focal_Adhesion_Regulation/125826", "title"=>"Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-01 01:37:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/643964"], "description"=>"<p>Nascent focal adhesions have a smaller area and are primarily responsible for generating traction and participate in generating contractile forces that allow cells to move. Mature focal adhesions have a larger area and are responsible for remodeling the extracellular matrix during migration. Primary human GB cells immunostained for focal adhesion proteins vinculin and paxillin. (A) Left panel, schematic representation of NKCC1, CD44, and NHE1 showing the localization of putative ezrin-radixin-moesin binding domains (red boxes) in the juxtamembranous intracellular domains of these proteins. Right panel, alignment of the protein sequences of NKCC1 of human (NP_001037), mouse (NP_033220), and rat (NP_113986) with the sequence of CD44 (NP_000601) and NHE1 (NP_003038), which have been shown to bind ezrin-radixin-moesin proteins to anchor the actin cytoskeleton to the plasma membrane. In these protein sequences, the positive amino acids such as lysine (K) and arginine (R) are highlighted in red; groups of three positive amino acids are underlined in blue and groups of two positive amino acids are underlined in green. (B–C) NS 318 control shRNA (left panel), NKCC1 shRNA (middle panel), and wild-type treated with 5 µM paclitaxel (right panel) stained with an anti-vinculin antibody (B) and anti-paxillin antibody (C) to visualize focal adhesions (lower panels in B and C show an amplification of areas within the squares). (D) Bar chart of the quantification of focal adhesion area stained with vinculin (<i>left panel</i>) and paxillin (<i>right panel</i>) antibodies. Quantification of vinculin staining NS318 control shRNA <i>n</i> = 23 cells, NS 318 NKCC1 shRNA <i>n</i> = 26 cells, NS 318 control shRNA+paclitaxel <i>n</i> = 22 cells, NS 501 control shRNA <i>n</i> = 20 cells, NS 501 NKCC1 shRNA <i>n</i> = 20 cells, and NS 501 control shRNA+paclitaxel <i>n</i> = 10 cells. Quantification of paxillin staining NS 318 control shRNA <i>n</i> = 21 cells, NS 318 NKCC1 shRNA <i>n</i> = 15 cells, NS 318 control shRNA+paclitaxel <i>n</i> = 21 cells, NS 501 control shRNA <i>n</i> = 12 cells, NS 501 NKCC1 shRNA <i>n</i> = 24 cells, and NS 501 control shRNA+paclitaxel <i>n</i> = 10 cells. * <i>p</i> value<0.05; ** <i>p</i> value<0.01. Scale bars represent 50 µm.</p>", "links"=>[], "tags"=>["knockdown", "increases", "focal", "adhesions", "gb"], "article_id"=>314442, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g004", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_knockdown_increases_the_size_of_focal_adhesions_in_primary_human_GB_cell_lines_/314442", "title"=>"NKCC1 knockdown increases the size of focal adhesions in primary human GB cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:14:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/644105"], "description"=>"<p>(A and B) Representative traction maps of GB cells stably expressing control shRNA or NKCC1 shRNA, respectively. The white line shows the cell boundary. Colors show the magnitude of the tractions in Pascal (Pa). Arrows show the direction and relative magnitude of the tractions. Scale bars represent 50 µm. Inset, phase contrast images of the respective cells on the elastic gel. Computed net contractile moment of GB cells expressing control shRNA or NKCC1 shRNA in (C), NS 561 (control shRNA <i>n</i> = 15 cells, NKCC1 shRNA <i>n</i> = 14 cells, <i>p</i> = 0.024) and (D) NS 501 (control shRNA <i>n</i> = 13 cells, NKCC1 shRNA <i>n</i> = 12 cells, <i>p</i> = 0.005). Net contractile moment is expressed in pico-Newton meter (pNm). Measurement of the projected cell area in µm<sup>2</sup> of (E) NS 561 (control shRNA versus NKCC1 shRNA, <i>p</i> = 0.01) and (F) NS 501 (control shRNA versus NKCC1 shRNA, <i>p</i> = 0.001). Data are presented as geometric mean ± SEM in log transformation.</p>", "links"=>[], "tags"=>["knockdown", "decreases", "contractile", "projected", "gb"], "article_id"=>314579, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g005", "stats"=>{"downloads"=>0, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_knockdown_decreases_the_net_contractile_moment_and_projected_area_in_primary_human_GB_cell_lines_/314579", "title"=>"NKCC1 knockdown decreases the net contractile moment and projected area in primary human GB cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:16:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/644503"], "description"=>"<p>(A) Treatment of GB cell lines NS 318 and NS 567 with EGF (30 ng/ml) stimulates phosphorylation of NKCC1. Exposure of cells to EGF (30 ng/ml) for 10, 30, and 60 min show a time-dependent course of NKCC1 phosphorylation. Also, exposure of NS 567 to 60 ng/ml of EGF shows higher levels of phosphorylation than phosphorylation levels at the same time point at 30 ng/ml showing a dose-dependent effect. A line plot is presented with the quantification of the ratio of p-NKCC1/NKCC1. (B) Activation of PI3K is necessary for phosphorylation of NKCC1 after stimulation of HEK-293 cells with EGF. HEK-293 cells were serum starved overnight and were incubated with wortmannin (WM) for 30 min prior to stimulation with EGF for 30 min. Total cell lysate (150 µg) was immunoprecipitated with T4 antibody before immunoblotting with anti-phospho NKCC1 antibody (top panel) or T4 antibody (bottom panel). (C) Activation of PI3K is necessary for increased phosphorylation of WNK3 after stimulation with 30 ng/ml EGF. After overnight serum starvation, HEK-293 cells were incubated with WM for 30 min prior to stimulation with EGF for 30 min. Total cell lysate (150 µg) was immunoprecipitated with WNK3 antibody before immunoblotting with anti-phosphorylated Akt substrate (αPAS) antibody (top panel) or WNK3 (bottom panels). (D) Total cell lysate samples (25 µg) were also resolved by SDS-PAGE and blotted with phospho-Akt (threonine 473, top panel) and Akt (bottom panel) antibodies to show inhibition of Akt phosphorylation after PI3K inhibition. A line plot is presented with the quantification of the ratio of p-NKCC1/NKCC1, αPAS/WNK3, and p-Akt/Akt. (E) Akt phosphorylation motif, top panel. Middle panel shows the alignment of the sequences of rat and human WNK3 showing conservation of the Akt phosphorylation motif. Bottom panel shows sequence of WNK1, which is phosphorylated by Akt (bottom panel) <a href=\"http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001320#pbio.1001320-Jiang1\" target=\"_blank\">[29]</a>. Conserved residues are highlighted in red letters.</p>", "links"=>[], "tags"=>["phosphorylation", "activation", "pi3k-akt", "pathway", "egf-mediated", "wnk3"], "article_id"=>314980, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g008", "stats"=>{"downloads"=>5, "page_views"=>78, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_EGF_promotes_phosphorylation_of_NKCC1_and_activation_of_the_PI3K_Akt_pathway_is_necessary_for_EGF_mediated_WNK3_phosphorylation_/314980", "title"=>"EGF promotes phosphorylation of NKCC1, and activation of the PI3K-Akt pathway is necessary for EGF-mediated WNK3 phosphorylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:23:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/644198"], "description"=>"<p>(A) Immunoprecipitation of NKCC1 in two GB cell lines shows that Ezrin and actin are associated with NKCC1. (B) Immunoprecipitation of Ezrin pulls down NKCC1 in several GB cell lines. (C) Cells that overexpress Ezrin-binding null NKCC1 generate lower contractile moments and have lower surface area. Black bars represent the transfected cells, and white bars represent the untransfected cells. Measured cells in the WT group (<i>n</i> = 16 untransfected cells; <i>n</i> = 11 transfected cells), and measured cells in the mutant group (<i>n</i> = 17 untransfected cells; <i>n</i> = 12 transfected cells). Bars represent mean ± S.E.M. * <i>p</i> value<0.001.</p>", "links"=>[], "tags"=>["affects", "contractile", "moments", "projected"], "article_id"=>314681, "categories"=>["Cancer", "Medicine", "Neuroscience"], "users"=>["Tomas Garzon-Muvdi", "Paula Schiapparelli", "Colette ap Rhys", "Hugo Guerrero-Cazares", "Christopher Smith", "Deok-Ho Kim", "Lyonell Kone", "Harrison Farber", "Danielle Y. Lee", "Steven S. An", "Andre Levchenko", "Alfredo Quinones-Hinojosa"], "doi"=>"https://dx.doi.org/10.1371/journal.pbio.1001320.g006", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NKCC1_Ezrin_association_affects_net_contractile_moments_and_projected_cell_area_/314681", "title"=>"NKCC1-Ezrin association affects net contractile moments and projected cell area.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-01 01:18:01"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"10", "full-text"=>"16", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"11", "full-text"=>"7", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
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  • {"unique-ip"=>"22", "full-text"=>"21", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
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  • {"unique-ip"=>"17", "full-text"=>"15", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"11", "full-text"=>"8", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"17", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"8", "full-text"=>"4", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"8", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"15", "full-text"=>"18", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"10", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"17", "full-text"=>"18", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"16", "full-text"=>"16", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"11", "full-text"=>"10", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"11", "full-text"=>"10", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"12", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"15", "full-text"=>"18", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
  • {"unique-ip"=>"16", "full-text"=>"20", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}

Relative Metric

{"start_date"=>"2012-01-01T00:00:00Z", "end_date"=>"2012-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[316, 541, 663, 766, 856, 950, 1041, 1128, 1218, 1302, 1382, 1456, 1526, 1593, 1657, 1729, 1796, 1862, 1930, 1999, 2065, 2132, 2202, 2261, 2319]}, {"subject_area"=>"/Biology and life sciences/Developmental biology", "average_usage"=>[313, 562, 690, 796, 893, 986, 1079, 1173, 1257, 1349, 1429, 1506, 1586, 1661, 1730, 1803, 1876, 1945, 2017, 2091, 2163, 2225, 2294, 2362, 2430]}]}
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