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  • Phosphorylation  (1,100)
  • American Association for the Advancement of Science (AAAS)  (1,100)
  • American Institute of Physics (AIP)
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  • 1
    Publication Date: 2016-02-26
    Description: In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2alpha eIF2alpha phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ben-Sahra, Issam -- Hoxhaj, Gerta -- Ricoult, Stephane J H -- Asara, John M -- Manning, Brendan D -- K99-CA194192/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01-CA120964/CA/NCI NIH HHS/ -- P30-CA006516/CA/NCI NIH HHS/ -- R01 CA181390/CA/NCI NIH HHS/ -- R01-CA181390/CA/NCI NIH HHS/ -- R35 CA197459/CA/NCI NIH HHS/ -- R35-CA197459/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):728-33. doi: 10.1126/science.aad0489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. bmanning@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912861" target="_blank"〉PubMed〈/a〉
    Keywords: Activating Transcription Factor 4/genetics/metabolism ; Animals ; Eukaryotic Initiation Factor-2/metabolism ; HEK293 Cells ; Humans ; Methenyltetrahydrofolate Cyclohydrolase/genetics ; Methylenetetrahydrofolate Dehydrogenase (NADP)/genetics ; Mice ; Mitochondria/*metabolism ; Multiprotein Complexes/genetics/*metabolism ; Phosphorylation ; Protein Biosynthesis ; Purines/*biosynthesis ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Tetrahydrofolates/*metabolism ; Transcription, Genetic
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  • 2
    Publication Date: 2016-04-09
    Description: Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaolei -- Ditlev, Jonathon A -- Hui, Enfu -- Xing, Wenmin -- Banjade, Sudeep -- Okrut, Julia -- King, David S -- Taunton, Jack -- Rosen, Michael K -- Vale, Ronald D -- 5-F32-DK101188/DK/NIDDK NIH HHS/ -- F32 DK101188/DK/NIDDK NIH HHS/ -- R01 GM056322/GM/NIGMS NIH HHS/ -- R01-GM56322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):595-9. doi: 10.1126/science.aad9964. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; HHMI Mass Spectrometry Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27056844" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Adaptor Proteins, Signal Transducing/*metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Jurkat Cells ; Membrane Proteins/*metabolism ; Mitogen-Activated Protein Kinase Kinases ; Phosphorylation ; Polymerization ; Receptors, Antigen, T-Cell/*agonists ; Signal Transduction ; T-Lymphocytes/*metabolism
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  • 3
    Publication Date: 2016-02-06
    Description: SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56beta, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidinosti, Michael -- Botta, Paolo -- Kruttner, Sebastian -- Proenca, Catia C -- Stoehr, Natacha -- Bernhard, Mario -- Fruh, Isabelle -- Mueller, Matthias -- Bonenfant, Debora -- Voshol, Hans -- Carbone, Walter -- Neal, Sarah J -- McTighe, Stephanie M -- Roma, Guglielmo -- Dolmetsch, Ricardo E -- Porter, Jeffrey A -- Caroni, Pico -- Bouwmeester, Tewis -- Luthi, Andreas -- Galimberti, Ivan -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1199-203. doi: 10.1126/science.aad5487. Epub 2016 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Friedrich Miescher Institute, Basel, Switzerland. ; Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA. ; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26847545" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autism Spectrum Disorder/*drug therapy/enzymology/genetics ; Chromosome Deletion ; Chromosome Disorders/genetics ; Chromosomes, Human, Pair 22/genetics ; Disease Models, Animal ; Down-Regulation ; Gene Knockdown Techniques ; Humans ; Insulin-Like Growth Factor I/metabolism ; Mice ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/*genetics ; Neurons/enzymology ; Phosphorylation ; Protein Phosphatase 2/metabolism ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism ; Proteomics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
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  • 4
    Publication Date: 2015-04-11
    Description: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das, Indrajit -- Krzyzosiak, Agnieszka -- Schneider, Kim -- Wrabetz, Lawrence -- D'Antonio, Maurizio -- Barry, Nicholas -- Sigurdardottir, Anna -- Bertolotti, Anne -- 309516/European Research Council/International -- MC_U105185860/Medical Research Council/United Kingdom -- R01-NS55256/NS/NINDS NIH HHS/ -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):239-42. doi: 10.1126/science.aaa4484.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859045" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Cells, Cultured ; Charcot-Marie-Tooth Disease/drug therapy/metabolism/pathology ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Inhibitors/metabolism/pharmacokinetics/*pharmacology/toxicity ; Guanabenz/*analogs & derivatives/chemical ; synthesis/metabolism/pharmacology/toxicity ; HeLa Cells ; Humans ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy ; Phosphorylation ; Protein Folding ; Protein Phosphatase 1/*antagonists & inhibitors ; Proteostasis Deficiencies/*drug therapy/*prevention & control ; Signal Transduction
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  • 5
    Publication Date: 2015-02-01
    Description: During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Siqi -- Cai, Xin -- Wu, Jiaxi -- Cong, Qian -- Chen, Xiang -- Li, Tuo -- Du, Fenghe -- Ren, Junyao -- Wu, You-Tong -- Grishin, Nick V -- Chen, Zhijian J -- AI-93967/AI/NIAID NIH HHS/ -- GM-094575/GM/NIGMS NIH HHS/ -- GM-63692/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25636800" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/*metabolism ; Adaptor Proteins, Vesicular Transport/chemistry/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Humans ; I-kappa B Kinase/metabolism ; Interferon Regulatory Factor-3/chemistry/*metabolism ; Interferon-alpha/biosynthesis ; Interferon-beta/biosynthesis ; Membrane Proteins/chemistry/*metabolism ; Mice ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/metabolism ; Sendai virus/physiology ; Serine/metabolism ; Signal Transduction ; Ubiquitination ; Vesiculovirus/physiology
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  • 6
    Publication Date: 2015-01-31
    Description: The mechanistic basis of eukaryotic circadian oscillators in model systems as diverse as Neurospora, Drosophila, and mammalian cells is thought to be a transcription-and-translation-based negative feedback loop, wherein progressive and controlled phosphorylation of one or more negative elements ultimately elicits their own proteasome-mediated degradation, thereby releasing negative feedback and determining circadian period length. The Neurospora crassa circadian negative element FREQUENCY (FRQ) exemplifies such proteins; it is progressively phosphorylated at more than 100 sites, and strains bearing alleles of frq with anomalous phosphorylation display abnormal stability of FRQ that is well correlated with altered periods or apparent arrhythmicity. Unexpectedly, we unveiled normal circadian oscillations that reflect the allelic state of frq but that persist in the absence of typical degradation of FRQ. This manifest uncoupling of negative element turnover from circadian period length determination is not consistent with the consensus eukaryotic circadian model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Larrondo, Luis F -- Olivares-Yanez, Consuelo -- Baker, Christopher L -- Loros, Jennifer J -- Dunlap, Jay C -- P01 GM68087/GM/NIGMS NIH HHS/ -- R01 GM034985/GM/NIGMS NIH HHS/ -- R01 GM083336/GM/NIGMS NIH HHS/ -- R01 GM34985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):1257277. doi: 10.1126/science.1257277.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635104" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/pharmacology ; Alleles ; *Circadian Clocks ; *Circadian Rhythm ; Feedback, Physiological ; Fungal Proteins/biosynthesis/*genetics/*metabolism ; Half-Life ; Neurospora crassa/*physiology ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Stability ; Proteolysis ; Signal Transduction
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  • 7
    Publication Date: 2015-06-27
    Description: Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ~24-hour rhythms. The clock of cyanobacteria is driven by a three-protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Yong-Gang -- Cohen, Susan E -- Phong, Connie -- Myers, William K -- Kim, Yong-Ick -- Tseng, Roger -- Lin, Jenny -- Zhang, Li -- Boyd, Joseph S -- Lee, Yvonne -- Kang, Shannon -- Lee, David -- Li, Sheng -- Britt, R David -- Rust, Michael J -- Golden, Susan S -- LiWang, Andy -- AI081982/AI/NIAID NIH HHS/ -- AI101436/AI/NIAID NIH HHS/ -- GM062419/GM/NIGMS NIH HHS/ -- GM100116/GM/NIGMS NIH HHS/ -- GM107521/GM/NIGMS NIH HHS/ -- R01 GM062419/GM/NIGMS NIH HHS/ -- R01 GM100116/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):324-8. doi: 10.1126/science.1260031. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Natural Sciences, University of California, Merced, CA 95343, USA. ; Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA. ; Department of Chemistry, University of California, Davis, CA 95616, USA. ; School of Natural Sciences, University of California, Merced, CA 95343, USA. Quantitative and Systems Biology, University of California, Merced, CA 95343, USA. ; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. ; Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; School of Natural Sciences, University of California, Merced, CA 95343, USA. Center for Circadian Biology, University of California, San Diego, La Jolla, CA 92093, USA. Quantitative and Systems Biology, University of California, Merced, CA 95343, USA. Chemistry and Chemical Biology, University of California, Merced, CA 95343, USA. Health Sciences Research Institute, University of California, Merced, CA 95343, USA. aliwang@ucmerced.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113641" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics/*metabolism ; *Circadian Rhythm ; Circadian Rhythm Signaling Peptides and Proteins/*chemistry/genetics/*metabolism ; Phosphorylation ; Protein Folding ; Protein Structure, Secondary ; Synechococcus/metabolism/*physiology
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  • 8
    Publication Date: 2015-06-13
    Description: Cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules through kinetochores and the spindle assembly checkpoint (SAC) is satisfied. We show that the amino-terminal localization module of the SAC protein kinase MPS1 (monopolar spindle 1) directly interacts with the HEC1 (highly expressed in cancer 1) calponin homology domain in the NDC80 (nuclear division cycle 80) kinetochore complex in vitro, in a phosphorylation-dependent manner. Microtubule polymers disrupted this interaction. In cells, MPS1 binding to kinetochores or to ectopic NDC80 complexes was prevented by end-on microtubule attachment, independent of known kinetochore protein-removal mechanisms. Competition for kinetochore binding between SAC proteins and microtubules provides a direct and perhaps evolutionarily conserved way to detect a properly organized spindle ready for cell division.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hiruma, Yoshitaka -- Sacristan, Carlos -- Pachis, Spyridon T -- Adamopoulos, Athanassios -- Kuijt, Timo -- Ubbink, Marcellus -- von Castelmur, Eleonore -- Perrakis, Anastassis -- Kops, Geert J P L -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1264-7. doi: 10.1126/science.aaa4055. Epub 2015 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Leiden Institute of Chemistry, Leiden University, Post Office Box 9502, 2300 RA Leiden, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068855" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Binding, Competitive ; Calcium-Binding Proteins/genetics/metabolism ; *Cell Cycle Checkpoints ; Cell Cycle Proteins/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microfilament Proteins/genetics/metabolism ; Microtubules/*metabolism ; Nuclear Proteins/chemistry/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Signal Transduction ; Spindle Apparatus/*metabolism
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  • 9
    Publication Date: 2015-05-16
    Description: The centrosome organizes microtubule arrays within animal cells and comprises two centrioles surrounded by an amorphous protein mass called the pericentriolar material (PCM). Despite the importance of centrosomes as microtubule-organizing centers, the mechanism and regulation of PCM assembly are not well understood. In Caenorhabditis elegans, PCM assembly requires the coiled-coil protein SPD-5. We found that recombinant SPD-5 could polymerize to form micrometer-sized porous networks in vitro. Network assembly was accelerated by two conserved regulators that control PCM assembly in vivo, Polo-like kinase-1 and SPD-2/Cep192. Only the assembled SPD-5 networks, and not unassembled SPD-5 protein, functioned as a scaffold for other PCM proteins. Thus, PCM size and binding capacity emerge from the regulated polymerization of one coiled-coil protein to form a porous network.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Woodruff, Jeffrey B -- Wueseke, Oliver -- Viscardi, Valeria -- Mahamid, Julia -- Ochoa, Stacy D -- Bunkenborg, Jakob -- Widlund, Per O -- Pozniakovsky, Andrei -- Zanin, Esther -- Bahmanyar, Shirin -- Zinke, Andrea -- Hong, Sun Hae -- Decker, Marcus -- Baumeister, Wolfgang -- Andersen, Jens S -- Oegema, Karen -- Hyman, Anthony A -- R01-GM074207/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 May 15;348(6236):808-12. doi: 10.1126/science.aaa3923.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. ; Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, Martinsried 82152, Germany. ; Department of Clinical Biochemistry, Copenhagen University Hospital, Hvidovre 2650, Denmark. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark. ; Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. hyman@mpi-cbg.de koegema@ucsd.edu. ; Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. hyman@mpi-cbg.de koegema@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25977552" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/*genetics/*metabolism ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/genetics/*metabolism ; Centrosome/*metabolism/ultrasonography ; Metabolic Networks and Pathways ; Phosphorylation ; Polymerization ; Protein Binding ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism
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  • 10
    Publication Date: 2015-12-15
    Description: Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Ming -- Yang, Wenjing -- Ni, Ting -- Tang, Zhanyun -- Nakadai, Tomoyoshi -- Zhu, Jun -- Roeder, Robert G -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1383-6. doi: 10.1126/science.aad2338.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. ; Systems Biology Center, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. ; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200438, P.R. China. ; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA. roeder@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26659056" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cyclin-Dependent Kinase 9/metabolism ; Cyclin-Dependent Kinases/metabolism ; *Gene Expression Regulation ; Humans ; Nuclear Proteins/genetics/*metabolism ; Phosphorylation ; Positive Transcriptional Elongation Factor B/metabolism ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; RNA Polymerase II/chemistry/genetics/*metabolism ; *Transcription Elongation, Genetic ; Transcription Factors/metabolism
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  • 11
    Publication Date: 2014-03-22
    Description: Biological oscillations are observed at many levels of cellular organization. In the social amoeba Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cyclic adenosine 3',5'-monophosphate (cAMP) waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor-mediated phosphorylation. Although both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit filters out high-frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061987/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061987/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cai, Huaqing -- Katoh-Kurasawa, Mariko -- Muramoto, Tetsuya -- Santhanam, Balaji -- Long, Yu -- Li, Lei -- Ueda, Masahiro -- Iglesias, Pablo A -- Shaulsky, Gad -- Devreotes, Peter N -- GM 28007/GM/NIGMS NIH HHS/ -- GM 34933/GM/NIGMS NIH HHS/ -- HD 039691/HD/NICHD NIH HHS/ -- P01 HD039691/HD/NICHD NIH HHS/ -- R01 GM028007/GM/NIGMS NIH HHS/ -- R01 GM034933/GM/NIGMS NIH HHS/ -- R37 GM028007/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1249531. doi: 10.1126/science.1249531.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24653039" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Cell Nucleus/*metabolism ; Cyclic AMP/metabolism/pharmacology ; Cytoplasm/*metabolism ; Dictyostelium/growth & development/*metabolism ; GATA Transcription Factors/chemistry/genetics/*metabolism ; Gene Expression Regulation ; Heterotrimeric GTP-Binding Proteins/metabolism ; Nuclear Localization Signals ; Phosphorylation ; Protozoan Proteins/chemistry/genetics/*metabolism ; Receptors, G-Protein-Coupled/metabolism
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  • 12
    Publication Date: 2014-03-15
    Description: Innate immunity relies on the perception of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) located on the host cell's surface. Many plant PRRs are kinases. Here, we report that the Arabidopsis receptor kinase EF-TU RECEPTOR (EFR), which perceives the elf18 peptide derived from bacterial elongation factor Tu, is activated upon ligand binding by phosphorylation on its tyrosine residues. Phosphorylation of a single tyrosine residue, Y836, is required for activation of EFR and downstream immunity to the phytopathogenic bacterium Pseudomonas syringae. A tyrosine phosphatase, HopAO1, secreted by P. syringae, reduces EFR phosphorylation and prevents subsequent immune responses. Thus, host and pathogen compete to take control of PRR tyrosine phosphorylation used to initiate antibacterial immunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macho, Alberto P -- Schwessinger, Benjamin -- Ntoukakis, Vardis -- Brutus, Alexandre -- Segonzac, Cecile -- Roy, Sonali -- Kadota, Yasuhiro -- Oh, Man-Ho -- Sklenar, Jan -- Derbyshire, Paul -- Lozano-Duran, Rosa -- Malinovsky, Frederikke Gro -- Monaghan, Jacqueline -- Menke, Frank L -- Huber, Steven C -- He, Sheng Yang -- Zipfel, Cyril -- BB/G024944/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- R01AI060761/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1509-12. doi: 10.1126/science.1248849. Epub 2014 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Sainsbury Laboratory, Norwich Research Park, Norwich NR4 7UH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24625928" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*immunology/*microbiology ; Arabidopsis Proteins/agonists/*metabolism ; Bacterial Proteins/*metabolism ; Peptide Elongation Factor Tu/*metabolism ; Peptides/metabolism/pharmacology ; Phosphorylation ; Protein Tyrosine Phosphatases/*metabolism ; Pseudomonas syringae/enzymology/*pathogenicity ; Receptors, Pattern Recognition/agonists/*metabolism ; Tyrosine/metabolism
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  • 13
    Publication Date: 2014-08-02
    Description: Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459787/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwon, Ilmin -- Xiang, Siheng -- Kato, Masato -- Wu, Leeju -- Theodoropoulos, Pano -- Wang, Tao -- Kim, Jiwoong -- Yun, Jonghyun -- Xie, Yang -- McKnight, Steven L -- U01 GM107623/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1139-45. doi: 10.1126/science.1254917. Epub 2014 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Quantitative Biomedical Research Center, Department of Clinical Sciences, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. steven.mcknight@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25081482" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Astrocytes/*metabolism/pathology ; Cell Death ; Cell Nucleolus/*metabolism ; Cells, Cultured ; Dipeptides/genetics/*metabolism/pharmacology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Glutamate Plasma Membrane Transport Proteins/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Humans ; Hydrogel ; Phosphorylation ; Protein Biosynthesis ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proteins/*genetics ; RNA, Antisense/antagonists & inhibitors/biosynthesis ; RNA, Messenger/antagonists & inhibitors/biosynthesis ; RNA, Ribosomal/antagonists & inhibitors/biosynthesis ; Repetitive Sequences, Amino Acid ; Transcription, Genetic
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  • 14
    Publication Date: 2014-01-25
    Description: Plant cells are immobile; thus, plant growth and development depend on cell expansion rather than cell migration. The molecular mechanism by which the plasma membrane initiates changes in the cell expansion rate remains elusive. We found that a secreted peptide, RALF (rapid alkalinization factor), suppresses cell elongation of the primary root by activating the cell surface receptor FERONIA in Arabidopsis thaliana. A direct peptide-receptor interaction is supported by specific binding of RALF to FERONIA and reduced binding and insensitivity to RALF-induced growth inhibition in feronia mutants. Phosphoproteome measurements demonstrate that the RALF-FERONIA interaction causes phosphorylation of plasma membrane H(+)-adenosine triphosphatase 2 at Ser(899), mediating the inhibition of proton transport. The results reveal a molecular mechanism for RALF-induced extracellular alkalinization and a signaling pathway that regulates cell expansion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672726/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haruta, Miyoshi -- Sabat, Grzegorz -- Stecker, Kelly -- Minkoff, Benjamin B -- Sussman, Michael R -- 5T32HG002760/HG/NHGRI NIH HHS/ -- U54 GM074901/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 24;343(6169):408-11. doi: 10.1126/science.1244454.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biotechnology Center, University of Wisconsin, Madison, WI 53706, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24458638" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*cytology/metabolism ; Arabidopsis Proteins/*agonists/genetics/*metabolism ; *Cell Enlargement ; Cell Membrane/*enzymology ; Molecular Sequence Data ; Peptide Hormones/genetics/*metabolism ; Phosphorylation ; Phosphotransferases/genetics/metabolism ; Plant Cells/metabolism/physiology ; Plant Roots/cytology/metabolism ; Protein Binding ; Proteome/metabolism ; Proton-Translocating ATPases/*metabolism ; Serine/metabolism
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  • 15
    Publication Date: 2014-04-20
    Description: Long noncoding RNAs (lncRNAs) play important roles in diverse biological processes; however, few have been identified that regulate immune cell differentiation and function. Here, we identified lnc-DC, which was exclusively expressed in human conventional dendritic cells (DCs). Knockdown of lnc-DC impaired DC differentiation from human monocytes in vitro and from mouse bone marrow cells in vivo and reduced capacity of DCs to stimulate T cell activation. lnc-DC mediated these effects by activating the transcription factor STAT3 (signal transducer and activator of transcription 3). lnc-DC bound directly to STAT3 in the cytoplasm, which promoted STAT3 phosphorylation on tyrosine-705 by preventing STAT3 binding to and dephosphorylation by SHP1. Our work identifies a lncRNA that regulates DC differentiation and also broadens the known mechanisms of lncRNA action.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Pin -- Xue, Yiquan -- Han, Yanmei -- Lin, Li -- Wu, Cong -- Xu, Sheng -- Jiang, Zhengping -- Xu, Junfang -- Liu, Qiuyan -- Cao, Xuetao -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):310-3. doi: 10.1126/science.1251456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744378" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Differentiation ; Chromatin/metabolism ; Cytoplasm/metabolism ; Dendritic Cells/*cytology/*immunology/physiology ; Epigenesis, Genetic ; Gene Expression Regulation ; Histones/metabolism ; Humans ; Lymphocyte Activation ; Mice ; Monocytes/cytology ; Nucleic Acid Conformation ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; RNA, Long Noncoding/*metabolism ; STAT3 Transcription Factor/*metabolism ; T-Lymphocytes/immunology
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  • 16
    Publication Date: 2014-11-08
    Description: Mitochondria play central roles in cellular energy conversion, metabolism, and apoptosis. Mitochondria import more than 1000 different proteins from the cytosol. It is unknown if the mitochondrial protein import machinery is connected to the cell division cycle. We found that the cyclin-dependent kinase Cdk1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. The molecular mechanism involved phosphorylation of the cytosolic precursor of Tom6 by cyclin Clb3-activated Cdk1, leading to enhanced import of Tom6 into mitochondria. Tom6 phosphorylation promoted assembly of the protein import channel Tom40 and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Tom6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harbauer, Angelika B -- Opalinska, Magdalena -- Gerbeth, Carolin -- Herman, Josip S -- Rao, Sanjana -- Schonfisch, Birgit -- Guiard, Bernard -- Schmidt, Oliver -- Pfanner, Nikolaus -- Meisinger, Chris -- New York, N.Y. -- Science. 2014 Nov 28;346(6213):1109-13. doi: 10.1126/science.1261253. Epub 2014 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Trinationales Graduiertenkolleg 1478, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Trinationales Graduiertenkolleg 1478, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. Faculty of Biology, Universitat Freiburg, 79104 Freiburg, Germany. Spemann Graduate School of Biology and Medicine, Universitat Freiburg, 79104 Freiburg, Germany. ; Centre de Genetique Moleculaire, CNRS, 91190 Gif-sur-Yvette, France. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Institut fur Biochemie und Molekularbiologie, ZBMZ, Universitat Freiburg, 79104 Freiburg, Germany. BIOSS Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. nikolaus.pfanner@biochemie.uni-freiburg.de chris.meisinger@biochemie.uni-freiburg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25378463" target="_blank"〉PubMed〈/a〉
    Keywords: CDC2 Protein Kinase/metabolism ; *Cell Cycle ; Cyclin B/metabolism ; Cytosol/metabolism ; Mitochondria/*metabolism ; Mitochondrial Membrane Transport Proteins/*metabolism ; Phosphorylation ; Protein Precursors/*metabolism ; Protein Transport ; Saccharomyces cerevisiae/*cytology/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism
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  • 17
    Publication Date: 2014-06-07
    Description: After light-induced nuclear translocation, phytochrome photoreceptors interact with and induce rapid phosphorylation and degradation of basic helix-loop-helix transcription factors, such as PHYTOCHROME-INTERACTING FACTOR 3 (PIF3), to regulate gene expression. Concomitantly, this interaction triggers feedback reduction of phytochrome B (phyB) levels. Light-induced phosphorylation of PIF3 is necessary for the degradation of both proteins. We report that this PIF3 phosphorylation induces, and is necessary for, recruitment of LRB [Light-Response Bric-a-Brack/Tramtrack/Broad (BTB)] E3 ubiquitin ligases to the PIF3-phyB complex. The recruited LRBs promote concurrent polyubiqutination and degradation of both PIF3 and phyB in vivo. These data reveal a linked signal-transmission and attenuation mechanism involving mutually assured destruction of the receptor and its immediate signaling partner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414656/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414656/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ni, Weimin -- Xu, Shou-Ling -- Tepperman, James M -- Stanley, David J -- Maltby, Dave A -- Gross, John D -- Burlingame, Alma L -- Wang, Zhi-Yong -- Quail, Peter H -- 2R01 GM-047475/GM/NIGMS NIH HHS/ -- 5R01GM066258/GM/NIGMS NIH HHS/ -- 8P41GM103481/GM/NIGMS NIH HHS/ -- P41 GM103481/GM/NIGMS NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- R01 GM047475/GM/NIGMS NIH HHS/ -- R01 GM066258/GM/NIGMS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1160-4. doi: 10.1126/science.1250778.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Plant Gene Expression Center, Agriculture Research Service (ARS), U.S. Department of Agriculture (USDA), Albany, CA 94710, USA. ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Plant Biology, Carnegie Institution for Science, Stanford, CA 94305, USA. ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. ; Department of Plant Biology, Carnegie Institution for Science, Stanford, CA 94305, USA. ; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Plant Gene Expression Center, Agriculture Research Service (ARS), U.S. Department of Agriculture (USDA), Albany, CA 94710, USA. quail@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904166" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Arabidopsis/genetics/*growth & development/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Cell Nucleus/metabolism ; Cullin Proteins/*metabolism ; Gene Expression Regulation, Plant ; HeLa Cells ; Humans ; *Light Signal Transduction ; Nuclear Proteins/genetics/metabolism ; Phosphorylation ; Phytochrome B/*metabolism ; Polyubiquitin/metabolism ; Proteolysis ; *Ubiquitination
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  • 18
    Publication Date: 2014-02-08
    Description: Despite our understanding of actomyosin function in individual migrating cells, we know little about the mechanisms by which actomyosin drives collective cell movement in vertebrate embryos. The collective movements of convergent extension drive both global reorganization of the early embryo and local remodeling during organogenesis. We report here that planar cell polarity (PCP) proteins control convergent extension by exploiting an evolutionarily ancient function of the septin cytoskeleton. By directing septin-mediated compartmentalization of cortical actomyosin, PCP proteins coordinate the specific shortening of mesenchymal cell-cell contacts, which in turn powers cell interdigitation. These data illuminate the interface between developmental signaling systems and the fundamental machinery of cell behavior and should provide insights into the etiology of human birth defects, such as spina bifida and congenital kidney cysts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167615/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167615/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shindo, Asako -- Wallingford, John B -- R01 GM074104/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):649-52. doi: 10.1126/science.1243126.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and University of Texas at Austin, Austin, TX 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24503851" target="_blank"〉PubMed〈/a〉
    Keywords: Actomyosin/*metabolism ; Animals ; *Cell Movement ; *Cell Polarity ; Embryo, Nonmammalian/cytology/metabolism ; Female ; Gastrula/cytology/metabolism ; Gene Knockdown Techniques ; Humans ; Mesoderm/cytology/metabolism ; Organogenesis ; Phosphorylation ; Septins/genetics/*metabolism ; Xenopus Proteins/genetics/*metabolism ; Xenopus laevis
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 19
    Publication Date: 2014-05-17
    Description: A switchlike response in nuclear factor-kappaB (NF-kappaB) activity implies the existence of a threshold in the NF-kappaB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-kappaB (IkappaB) kinase-beta (IKKbeta) module is a switch mechanism for NF-kappaB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKbeta to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKbeta target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-kappaB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinohara, Hisaaki -- Behar, Marcelo -- Inoue, Kentaro -- Hiroshima, Michio -- Yasuda, Tomoharu -- Nagashima, Takeshi -- Kimura, Shuhei -- Sanjo, Hideki -- Maeda, Shiori -- Yumoto, Noriko -- Ki, Sewon -- Akira, Shizuo -- Sako, Yasushi -- Hoffmann, Alexander -- Kurosaki, Tomohiro -- Okada-Hatakeyama, Mariko -- 5R01CA141722/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 May 16;344(6185):760-4. doi: 10.1126/science.1250020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ; Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center (QBiC), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Graduate School of Engineering, Tottori University 4-101, Koyama-minami, Tottori 680-8552, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ; Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833394" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/metabolism ; CARD Signaling Adaptor Proteins/genetics/*metabolism ; Cell Line ; Chickens ; Feedback, Physiological ; Guanylate Cyclase/genetics/*metabolism ; I-kappa B Kinase/*metabolism ; MAP Kinase Kinase Kinases/genetics/*metabolism ; Mice ; Mice, Knockout ; Mutation ; NF-kappa B/*agonists ; Phosphorylation ; Receptors, Antigen, B-Cell/genetics/*metabolism ; Serine/genetics/metabolism ; Signal Transduction
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  • 20
    Publication Date: 2014-01-05
    Description: Metaphase chromosomes are visible hallmarks of mitosis, yet our understanding of their structure and of the forces shaping them is rudimentary. Phosphorylation of histone H3 serine 10 (H3 S10) by Aurora B kinase is a signature event of mitosis, but its function in chromatin condensation is unclear. Using genetically encoded ultraviolet light-inducible cross-linkers, we monitored protein-protein interactions with spatiotemporal resolution in living yeast to identify the molecular details of the pathway downstream of H3 S10 phosphorylation. This modification leads to the recruitment of the histone deacetylase Hst2p that subsequently removes an acetyl group from histone H4 lysine 16, freeing the H4 tail to interact with the surface of neighboring nucleosomes and promoting fiber condensation. This cascade of events provides a condensin-independent driving force of chromatin hypercondensation during mitosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilkins, Bryan J -- Rall, Nils A -- Ostwal, Yogesh -- Kruitwagen, Tom -- Hiragami-Hamada, Kyoko -- Winkler, Marco -- Barral, Yves -- Fischle, Wolfgang -- Neumann, Heinz -- New York, N.Y. -- Science. 2014 Jan 3;343(6166):77-80. doi: 10.1126/science.1244508.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Free Floater (Junior) Research Group "Applied Synthetic Biology," Institute for Microbiology and Genetics, Georg-August University Gottingen, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24385627" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Chromatin/*metabolism ; Chromosomes, Fungal/genetics/metabolism ; Cross-Linking Reagents/chemistry/radiation effects ; DNA-Binding Proteins/metabolism ; Histones/*metabolism ; Lysine/metabolism ; *Mitosis ; Multiprotein Complexes/metabolism ; Phosphorylation ; Protein Interaction Mapping ; *Protein Processing, Post-Translational ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Serine/*metabolism ; Sirtuin 2/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 21
    Publication Date: 2014-09-23
    Description: Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnaoutov, Alexei -- Dasso, Mary -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1512-5. doi: 10.1126/science.1251550.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. arnaouta@mail.nih.gov. ; Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237103" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalytic Domain ; Deoxyadenine Nucleotides/*metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Lectins, C-Type/genetics/*metabolism ; Membrane Proteins/genetics/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Ribonucleotide Reductases/*antagonists & inhibitors/metabolism
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  • 22
    Publication Date: 2014-01-18
    Description: Btk29A is the Drosophila ortholog of the mammalian Bruton's tyrosine kinase (Btk), mutations of which in humans cause a heritable immunodeficiency disease. Btk29A mutations stabilized the proliferating cystoblast fate, leading to an ovarian tumor. This phenotype was rescued by overexpression of wild-type Btk29A and phenocopied by the interference of Wnt4-beta-catenin signaling or its putative downstream nuclear protein Piwi in somatic escort cells. Btk29A and mammalian Btk directly phosphorylated tyrosine residues of beta-catenin, leading to the up-regulation of its transcriptional activity. Thus, we identify a transcriptional switch involving the kinase Btk29A/Btk and its phosphorylation target, beta-catenin, which functions downstream of Wnt4 in escort cells to terminate Drosophila germ cell proliferation through up-regulation of piwi expression. This signaling mechanism likely represents a versatile developmental switch.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamada-Kawaguchi, Noriko -- Nore, Beston F -- Kuwada, Yusuke -- Smith, C I Edvard -- Yamamoto, Daisuke -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):294-7. doi: 10.1126/science.1244512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology and Neurosciences, Tohoku University Graduate School of Life Sciences, Sendai 980-8577, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436419" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/*biosynthesis ; *Cell Proliferation ; DNA Breaks, Double-Stranded ; Drosophila Proteins/*biosynthesis/genetics/*metabolism ; Drosophila melanogaster/genetics/metabolism/*physiology ; Gene Knockdown Techniques ; Genomic Instability ; Germ Cells/cytology/metabolism/*physiology ; Glycoproteins/genetics/*metabolism ; Phosphorylation ; Protein-Tyrosine Kinases/genetics/*metabolism ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Transcription, Genetic ; Tyrosine/genetics/metabolism ; Up-Regulation ; Wnt Proteins/genetics/*metabolism ; beta Catenin/genetics/*metabolism
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  • 23
    Publication Date: 2013-11-16
    Description: The microtubule-based mitotic spindle segregates chromosomes during cell division. During chromosome segregation, the centromeric regions of chromosomes build kinetochores that establish end-coupled attachments to spindle microtubules. Here, we used the Caenorhabditis elegans embryo as a model system to examine the crosstalk between two kinetochore protein complexes implicated in temporally distinct stages of attachment formation. The kinetochore dynein module, which mediates initial lateral microtubule capture, inhibited microtubule binding by the Ndc80 complex, which ultimately forms the end-coupled attachments that segregate chromosomes. The kinetochore dynein module directly regulated Ndc80, independently of phosphorylation by Aurora B kinase, and this regulation was required for accurate segregation. Thus, the conversion from initial dynein-mediated, lateral attachments to correctly oriented, Ndc80-mediated end-coupled attachments is actively controlled.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885540/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheerambathur, Dhanya K -- Gassmann, Reto -- Cook, Brian -- Oegema, Karen -- Desai, Arshad -- GM074215/GM/NIGMS NIH HHS/ -- R01 GM074215/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1239-42. doi: 10.1126/science.1246232. Epub 2013 Nov 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24231804" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Aurora Kinase B/metabolism ; Caenorhabditis elegans/embryology ; Caenorhabditis elegans Proteins/chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/genetics/metabolism ; *Chromosome Segregation ; Dyneins/*metabolism ; Embryo, Nonmammalian/metabolism ; Kinetochores/*metabolism ; Microtubule-Associated Proteins/genetics/*metabolism ; Microtubules/*metabolism ; Multiprotein Complexes/metabolism ; Phenotype ; Phosphorylation ; Protein Binding ; Spindle Apparatus/*metabolism ; Transgenes
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  • 24
    Publication Date: 2013-04-27
    Description: Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774525/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774525/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Yun -- Dorn, Gerald W 2nd -- R01 HL059888/HL/NHLBI NIH HHS/ -- R21 HL107276/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Apr 26;340(6131):471-5. doi: 10.1126/science.1231031.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23620051" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autophagy ; Cardiomyopathies/enzymology ; Drosophila melanogaster ; Fibroblasts/ultrastructure ; GTP Phosphohydrolases/genetics/*metabolism ; HEK293 Cells ; Humans ; Mice ; Mice, Mutant Strains ; Mitochondria/enzymology ; Mitochondria, Heart/*enzymology ; Molecular Sequence Data ; Myocytes, Cardiac/*enzymology/ultrastructure ; Phosphorylation ; Protein Kinases/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; Ubiquitination
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  • 25
    Publication Date: 2013-07-28
    Description: Loss of function of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene is associated with many human cancers. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway. PTEN also accumulates in the nucleus, where its function remains poorly understood. We demonstrate that SUMOylation (SUMO, small ubiquitin-like modifier) of PTEN controls its nuclear localization. In cells exposed to genotoxic stress, SUMO-PTEN was rapidly excluded from the nucleus dependent on the protein kinase ataxia telangiectasia mutated (ATM). Cells lacking nuclear PTEN were hypersensitive to DNA damage, whereas PTEN-deficient cells were susceptible to killing by a combination of genotoxic stress and a small-molecule PI3K inhibitor both in vitro and in vivo. Our findings may have implications for individualized therapy for patients with PTEN-deficient tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bassi, C -- Ho, J -- Srikumar, T -- Dowling, R J O -- Gorrini, C -- Miller, S J -- Mak, T W -- Neel, B G -- Raught, B -- Stambolic, V -- R37 CA49152/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):395-9. doi: 10.1126/science.1236188.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888040" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Aminopyridines/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Nucleus/*enzymology/metabolism ; Cisplatin/pharmacology ; DNA Breaks, Double-Stranded ; *DNA Damage ; *DNA Repair ; DNA-Binding Proteins/metabolism ; Doxorubicin/pharmacology ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Morpholines/pharmacology ; Neoplasm Transplantation ; PTEN Phosphohydrolase/genetics/*metabolism ; Phosphatidylinositol 3-Kinase/antagonists & inhibitors ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Sumoylation ; Transplantation, Heterologous ; Tumor Suppressor Proteins/metabolism
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  • 26
    Publication Date: 2013-02-16
    Description: Casein kinase 1 (CK1) members play key roles in numerous biological processes. They are considered "rogue" kinases, because their enzymatic activity appears unregulated. Contrary to this notion, we have identified the DEAD-box RNA helicase DDX3 as a regulator of the Wnt-beta-catenin network, where it acts as a regulatory subunit of CK1epsilon: In a Wnt-dependent manner, DDX3 binds CK1epsilon and directly stimulates its kinase activity, and promotes phosphorylation of the scaffold protein dishevelled. DDX3 is required for Wnt-beta-catenin signaling in mammalian cells and during Xenopus and Caenorhabditis elegans development. The results also suggest that the kinase-stimulatory function extends to other DDX and CK1 members, opening fresh perspectives for one of the longest-studied protein kinase families.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruciat, Cristina-Maria -- Dolde, Christine -- de Groot, Reinoud E A -- Ohkawara, Bisei -- Reinhard, Carmen -- Korswagen, Hendrik C -- Niehrs, Christof -- New York, N.Y. -- Science. 2013 Mar 22;339(6126):1436-41. doi: 10.1126/science.1231499. Epub 2013 Feb 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23413191" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Caenorhabditis elegans/genetics/growth & development/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; Casein Kinase Iepsilon/chemistry/*metabolism ; DEAD-box RNA Helicases/chemistry/genetics/*metabolism ; HEK293 Cells ; Humans ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; RNA Helicases/chemistry/genetics/*metabolism ; Wnt Proteins/metabolism ; *Wnt Signaling Pathway ; Xenopus/embryology/genetics/metabolism ; Xenopus Proteins/chemistry/genetics/*metabolism ; beta Catenin/metabolism
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  • 27
    Publication Date: 2013-06-08
    Description: Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935617/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3935617/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hopkins, Benjamin D -- Fine, Barry -- Steinbach, Nicole -- Dendy, Meaghan -- Rapp, Zachary -- Shaw, Jacquelyn -- Pappas, Kyrie -- Yu, Jennifer S -- Hodakoski, Cindy -- Mense, Sarah -- Klein, Joshua -- Pegno, Sarah -- Sulis, Maria-Luisa -- Goldstein, Hannah -- Amendolara, Benjamin -- Lei, Liang -- Maurer, Matthew -- Bruce, Jeffrey -- Canoll, Peter -- Hibshoosh, Hanina -- Parsons, Ramon -- 2T32 CA09503/CA/NCI NIH HHS/ -- CA082783/CA/NCI NIH HHS/ -- CA097403/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- R01 CA082783/CA/NCI NIH HHS/ -- R01 CA155117/CA/NCI NIH HHS/ -- R01 NS066955/NS/NINDS NIH HHS/ -- R01 NS073610/NS/NINDS NIH HHS/ -- R01NS066955/NS/NINDS NIH HHS/ -- T32 CA009503/CA/NCI NIH HHS/ -- T32 GM008224/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):399-402. doi: 10.1126/science.1234907. Epub 2013 Jun 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23744781" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line, Tumor ; *Cell Survival ; Embryonic Stem Cells ; Glioblastoma/drug therapy/metabolism/pathology ; HEK293 Cells ; Humans ; Mice ; Mice, Nude ; Molecular Sequence Data ; Mutation ; PTEN Phosphohydrolase/*chemistry/genetics/*metabolism/pharmacology ; Peptide Chain Initiation, Translational ; Phosphatidylinositol 3-Kinase/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics/metabolism ; *Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
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  • 28
    Publication Date: 2013-01-12
    Description: DNA double-strand breaks (DSBs) represent a threat to the genome because they can lead to the loss of genetic information and chromosome rearrangements. The DNA repair protein p53 binding protein 1 (53BP1) protects the genome by limiting nucleolytic processing of DSBs by a mechanism that requires its phosphorylation, but whether 53BP1 does so directly is not known. Here, we identify Rap1-interacting factor 1 (Rif1) as an ATM (ataxia-telangiectasia mutated) phosphorylation-dependent interactor of 53BP1 and show that absence of Rif1 results in 5'-3' DNA-end resection in mice. Consistent with enhanced DNA resection, Rif1 deficiency impairs DNA repair in the G(1) and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815530/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815530/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Virgilio, Michela -- Callen, Elsa -- Yamane, Arito -- Zhang, Wenzhu -- Jankovic, Mila -- Gitlin, Alexander D -- Feldhahn, Niklas -- Resch, Wolfgang -- Oliveira, Thiago Y -- Chait, Brian T -- Nussenzweig, Andre -- Casellas, Rafael -- Robbiani, Davide F -- Nussenzweig, Michel C -- AI037526/AI/NIAID NIH HHS/ -- GM007739/GM/NIGMS NIH HHS/ -- GM103314/GM/NIGMS NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- RR00862/RR/NCRR NIH HHS/ -- RR022220/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2013 Feb 8;339(6120):711-5. doi: 10.1126/science.1230624. Epub 2013 Jan 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23306439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/immunology/metabolism ; Cell Cycle Proteins/antagonists & inhibitors/metabolism ; Cells, Cultured ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA/*metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair ; DNA-Binding Proteins/antagonists & inhibitors/*metabolism ; G1 Phase ; G2 Phase ; Genomic Instability ; *Immunoglobulin Class Switching ; Mice ; Phosphorylation ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; S Phase ; Telomere-Binding Proteins/*metabolism ; Tumor Suppressor Proteins/antagonists & inhibitors/metabolism
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  • 29
    Publication Date: 2013-04-13
    Description: Wnt signaling stabilizes beta-catenin through the LRP6 receptor signaling complex, which antagonizes the beta-catenin destruction complex. The Axin scaffold and associated glycogen synthase kinase-3 (GSK3) have central roles in both assemblies, but the transduction mechanism from the receptor to the destruction complex is contentious. We report that Wnt signaling is governed by phosphorylation regulation of the Axin scaffolding function. Phosphorylation by GSK3 kept Axin activated ("open") for beta-catenin interaction and poised for engagement of LRP6. Formation of the Wnt-induced LRP6-Axin signaling complex promoted Axin dephosphorylation by protein phosphatase-1 and inactivated ("closed") Axin through an intramolecular interaction. Inactivation of Axin diminished its association with beta-catenin and LRP6, thereby inhibiting beta-catenin phosphorylation and enabling activated LRP6 to selectively recruit active Axin for inactivation reiteratively. Our findings reveal mechanisms for scaffold regulation and morphogen signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788643/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Sung-Eun -- Huang, He -- Zhao, Ming -- Zhang, Xinjun -- Zhang, Aili -- Semonov, Mikhail V -- MacDonald, Bryan T -- Zhang, Xiaowu -- Garcia Abreu, Jose -- Peng, Leilei -- He, Xi -- P30 HD-18655/HD/NICHD NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- R00EB008737/EB/NIBIB NIH HHS/ -- R01 AR060359/AR/NIAMS NIH HHS/ -- R01 GM074241/GM/NIGMS NIH HHS/ -- R01EB015481/EB/NIBIB NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 May 17;340(6134):867-70. doi: 10.1126/science.1232389. Epub 2013 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉F. M. Kirby Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579495" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Axin Protein/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Low Density Lipoprotein Receptor-Related Protein-6/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Protein Stability ; Signal Transduction ; Wnt Proteins/*metabolism ; Xenopus ; beta Catenin/*metabolism
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  • 30
    Publication Date: 2013-01-26
    Description: Signaling pathways can induce different dynamics of transcription factor (TF) activation. We explored how TFs process signaling inputs to generate diverse dynamic responses. The budding yeast general stress-responsive TF Msn2 acted as a tunable signal processor that could track, filter, or integrate signals in an input-dependent manner. This tunable signal processing appears to originate from dual regulation of both nuclear import and export by phosphorylation, as mutants with one form of regulation sustained only one signal-processing function. Versatile signal processing by Msn2 is crucial for generating distinct dynamic responses to different natural stresses. Our findings reveal how complex signal-processing functions are integrated into a single molecule and provide a guide for the design of TFs with "programmable" signal-processing functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746486/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746486/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hao, Nan -- Budnik, Bogdan A -- Gunawardena, Jeremy -- O'Shea, Erin K -- R01 GM081578/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jan 25;339(6118):460-4. doi: 10.1126/science.1227299.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University Faculty of Arts and Sciences Center for Systems Biology, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23349292" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Cell Nucleus/*metabolism ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/genetics/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/*metabolism ; Models, Biological ; Nuclear Export Signals ; Nuclear Localization Signals ; Osmotic Pressure ; Oxidative Stress ; Phosphorylation ; Proteins/pharmacology ; Saccharomyces cerevisiae/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; *Signal Transduction ; Stress, Physiological ; Transcription Factors/*metabolism
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  • 31
    Publication Date: 2013-02-02
    Description: Receptor-interacting protein kinase 4 (RIPK4) is required for epidermal differentiation and is mutated in Bartsocas-Papas syndrome. RIPK4 binds to protein kinase C, but its signaling mechanisms are largely unknown. Ectopic RIPK4, but not catalytically inactive or Bartsocas-Papas RIPK4 mutants, induced accumulation of cytosolic beta-catenin and a transcriptional program similar to that caused by Wnt3a. In Xenopus embryos, Ripk4 synergized with coexpressed Xwnt8, whereas Ripk4 morpholinos or catalytic inactive Ripk4 antagonized Wnt signaling. RIPK4 interacted constitutively with the adaptor protein DVL2 and, after Wnt3a stimulation, with the co-receptor LRP6. Phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling. Wnt-dependent growth of xenografted human tumor cells was suppressed by RIPK4 knockdown, suggesting that RIPK4 overexpression may contribute to the growth of certain tumor types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094295/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094295/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, XiaoDong -- McGann, James C -- Liu, Bob Y -- Hannoush, Rami N -- Lill, Jennie R -- Pham, Victoria -- Newton, Kim -- Kakunda, Michael -- Liu, Jinfeng -- Yu, Christine -- Hymowitz, Sarah G -- Hongo, Jo-Anne -- Wynshaw-Boris, Anthony -- Polakis, Paul -- Harland, Richard M -- Dixit, Vishva M -- R01 GM042341/GM/NIGMS NIH HHS/ -- R01 NS073159/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2013 Mar 22;339(6126):1441-5. doi: 10.1126/science.1232253. Epub 2013 Jan 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23371553" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Cell Line ; Cell Line, Tumor ; Cytosol/metabolism ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Low Density Lipoprotein Receptor-Related Protein-6/metabolism ; Neoplasm Transplantation ; Neoplasms/metabolism ; Ovarian Neoplasms/metabolism ; Phosphoproteins/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Transplantation, Heterologous ; *Wnt Signaling Pathway ; Wnt3A Protein/metabolism ; Xenopus Proteins/genetics/*metabolism ; Xenopus laevis/embryology/metabolism ; beta Catenin/metabolism
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  • 32
    Publication Date: 2013-07-28
    Description: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Seong A -- Pacold, Michael E -- Cervantes, Christopher L -- Lim, Daniel -- Lou, Hua Jane -- Ottina, Kathleen -- Gray, Nathanael S -- Turk, Benjamin E -- Yaffe, Michael B -- Sabatini, David M -- AI047389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- GM59281/GM/NIGMS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Jul 26;341(6144):1236566. doi: 10.1126/science.1236566.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23888043" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acids/metabolism ; Animals ; Cell Line ; Culture Media ; Humans ; Mice ; Multiprotein Complexes ; Naphthyridines/pharmacology ; Peptides/chemistry/*metabolism ; Phosphorylation ; Proteins/antagonists & inhibitors/*chemistry/*metabolism ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism
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  • 33
    Publication Date: 2013-08-10
    Description: Phosphorylated O-mannosyl trisaccharide [N-acetylgalactosamine-beta3-N-acetylglucosamine-beta4-(phosphate-6-)mannose] is required for dystroglycan to bind laminin-G domain-containing extracellular proteins with high affinity in muscle and brain. However, the enzymes that produce this structure have not been fully elucidated. We found that glycosyltransferase-like domain-containing 2 (GTDC2) is a protein O-linked mannose beta 1,4-N-acetylglucosaminyltransferase whose product could be extended by beta 1,3-N-acetylgalactosaminyltransferase2 (B3GALNT2) to form the O-mannosyl trisaccharide. Furthermore, we identified SGK196 as an atypical kinase that phosphorylated the 6-position of O-mannose, specifically after the mannose had been modified by both GTDC2 and B3GALNT2. These findings suggest how mutations in GTDC2, B3GALNT2, and SGK196 disrupt dystroglycan receptor function and lead to congenital muscular dystrophy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshida-Moriguchi, Takako -- Willer, Tobias -- Anderson, Mary E -- Venzke, David -- Whyte, Tamieka -- Muntoni, Francesco -- Lee, Hane -- Nelson, Stanley F -- Yu, Liping -- Campbell, Kevin P -- 1U54NS053672/NS/NINDS NIH HHS/ -- MR/K000608/1/Medical Research Council/United Kingdom -- P30 AR057230/AR/NIAMS NIH HHS/ -- R01 HL079031/HL/NHLBI NIH HHS/ -- U54 NS053672/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):896-9. doi: 10.1126/science.1239951. Epub 2013 Aug 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242-1101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23929950" target="_blank"〉PubMed〈/a〉
    Keywords: Dystroglycans/*metabolism ; Glycosylation ; Glycosyltransferases/genetics/metabolism ; HEK293 Cells ; Humans ; N-Acetylgalactosaminyltransferases/genetics/metabolism ; N-Acetylglucosaminyltransferases/genetics/metabolism ; Phosphorylation ; Protein Kinases/genetics/*metabolism ; *Protein Processing, Post-Translational ; Trisaccharides/metabolism
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  • 34
    Publication Date: 2013-04-13
    Description: Scaffold-assisted signaling cascades guide cellular decision-making. In budding yeast, one such signal transduction pathway called the mitotic exit network (MEN) governs the transition from mitosis to the G1 phase of the cell cycle. The MEN is conserved and in metazoans is known as the Hippo tumor-suppressor pathway. We found that signaling through the MEN kinase cascade was mediated by an unusual two-step process. The MEN kinase Cdc15 first phosphorylated the scaffold Nud1. This created a phospho-docking site on Nud1, to which the effector kinase complex Dbf2-Mob1 bound through a phosphoserine-threonine binding domain, in order to be activated by Cdc15. This mechanism of pathway activation has implications for signal transmission through other kinase cascades and might represent a general principle in scaffold-assisted signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884217/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rock, Jeremy M -- Lim, Daniel -- Stach, Lasse -- Ogrodowicz, Roksana W -- Keck, Jamie M -- Jones, Michele H -- Wong, Catherine C L -- Yates, John R 3rd -- Winey, Mark -- Smerdon, Stephen J -- Yaffe, Michael B -- Amon, Angelika -- CA112967/CA/NCI NIH HHS/ -- ES015339/ES/NIEHS NIH HHS/ -- F32 GM086038/GM/NIGMS NIH HHS/ -- GM056800/GM/NIGMS NIH HHS/ -- GM51312/GM/NIGMS NIH HHS/ -- MC_U117584228/Medical Research Council/United Kingdom -- P30 CA014051/CA/NCI NIH HHS/ -- P41 GM103533/GM/NIGMS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 ES015339/ES/NIEHS NIH HHS/ -- R01 GM051312/GM/NIGMS NIH HHS/ -- R01 GM056800/GM/NIGMS NIH HHS/ -- R29 GM056800/GM/NIGMS NIH HHS/ -- U117584228/Medical Research Council/United Kingdom -- U54 CA112967/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 May 17;340(6134):871-5. doi: 10.1126/science.1235822. Epub 2013 Apr 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23579499" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Cell Cycle Proteins/chemistry/*metabolism ; Deoxyribonucleases/chemistry/*metabolism ; Enzyme Activation ; GTP-Binding Proteins/*metabolism ; *Mitosis ; Phosphoproteins/chemistry/*metabolism ; Phosphorylation ; Protein Conformation ; Protein-Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/cytology/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Signal Transduction ; tRNA Methyltransferases/chemistry/*metabolism
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  • 35
    Publication Date: 2012-06-02
    Description: Pattern recognition receptors confer plant resistance to pathogen infection by recognizing the conserved pathogen-associated molecular patterns. The cell surface receptor chitin elicitor receptor kinase 1 of Arabidopsis (AtCERK1) directly binds chitin through its lysine motif (LysM)-containing ectodomain (AtCERK1-ECD) to activate immune responses. The crystal structure that we solved of an AtCERK1-ECD complexed with a chitin pentamer reveals that their interaction is primarily mediated by a LysM and three chitin residues. By acting as a bivalent ligand, a chitin octamer induces AtCERK1-ECD dimerization that is inhibited by shorter chitin oligomers. A mutation attenuating chitin-induced AtCERK1-ECD dimerization or formation of nonproductive AtCERK1 dimer by overexpression of AtCERK1-ECD compromises AtCERK1-mediated signaling in plant cells. Together, our data support the notion that chitin-induced AtCERK1 dimerization is critical for its activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Tingting -- Liu, Zixu -- Song, Chuanjun -- Hu, Yunfei -- Han, Zhifu -- She, Ji -- Fan, Fangfang -- Wang, Jiawei -- Jin, Changwen -- Chang, Junbiao -- Zhou, Jian-Min -- Chai, Jijie -- New York, N.Y. -- Science. 2012 Jun 1;336(6085):1160-4. doi: 10.1126/science.1218867.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate Program in Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22654057" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/chemistry/metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Arabidopsis/immunology/*metabolism ; Arabidopsis Proteins/*chemistry/genetics/*metabolism ; Binding Sites ; Chitin/chemistry/*metabolism ; Crystallography, X-Ray ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Phosphorylation ; Plants, Genetically Modified ; Protein Multimerization ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/*chemistry/genetics/*metabolism ; Receptors, Pattern Recognition/*chemistry/genetics/*metabolism ; Signal Transduction
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  • 36
    Publication Date: 2012-11-01
    Description: Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507442/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507442/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Richard C -- Wei, Yongjie -- An, Zhenyi -- Zou, Zhongju -- Xiao, Guanghua -- Bhagat, Govind -- White, Michael -- Reichelt, Julia -- Levine, Beth -- K08 CA164047/CA/NCI NIH HHS/ -- P30 CA142543/CA/NCI NIH HHS/ -- R01 CA071443/CA/NCI NIH HHS/ -- R01 CA084254/CA/NCI NIH HHS/ -- R01 CA109618/CA/NCI NIH HHS/ -- R01 CA129451/CA/NCI NIH HHS/ -- R01 CA84254-S1/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Nov 16;338(6109):956-9. doi: 10.1126/science.1225967. Epub 2012 Oct 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23112296" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/genetics/*metabolism ; *Autophagy ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism ; Fibroblasts/metabolism/pathology ; HeLa Cells ; Humans ; Membrane Proteins/genetics/*metabolism ; Mice ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; RNA, Small Interfering/genetics ; Rats ; Transduction, Genetic ; Vimentin/genetics ; Xenograft Model Antitumor Assays
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  • 37
    Publication Date: 2012-05-05
    Description: Germinal centers (GCs) generate memory B and plasma cells, which are essential for long-lived humoral immunity. GC B cells with high-affinity B cell receptors (BCRs) are selectively expanded. To enable this selection, BCRs of such cells are thought to signal differently from those with lower affinity. We show that, surprisingly, most proliferating GC B cells did not demonstrate active BCR signaling. Rather, spontaneous and induced signaling was limited by increased phosphatase activity. Accordingly, both SH2 domain-containing phosphatase-1 (SHP-1) and SH2 domain-containing inositol 5 phosphatase were hyperphosphorylated in GC cells and remained colocalized with BCRs after ligation. Furthermore, SHP-1 was required for GC maintenance. Intriguingly, GC B cells in the cell-cycle G(2) period regained responsiveness to BCR stimulation. These data have implications for how higher-affinity B cells are selected in the GC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777391/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777391/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khalil, Ashraf M -- Cambier, John C -- Shlomchik, Mark J -- AI43603/AI/NIAID NIH HHS/ -- AR44077/AR/NIAMS NIH HHS/ -- R01 AI043603/AI/NIAID NIH HHS/ -- R01 AR044077/AR/NIAMS NIH HHS/ -- New York, N.Y. -- Science. 2012 Jun 1;336(6085):1178-81. doi: 10.1126/science.1213368. Epub 2012 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22555432" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Affinity ; Antigen Presentation ; Antigens/immunology ; Antigens, CD79/metabolism ; B-Lymphocytes/enzymology/*immunology/metabolism ; Calcium/metabolism ; Cell Cycle ; Down-Regulation ; Germinal Center/cytology/*immunology ; Intracellular Signaling Peptides and Proteins/metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ;