Sequential Phosphorylation of NDEL1 by the DYRK2-Gsk3b Complex Is
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The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy
International Journal of Molecular Sciences Review The Role of Z-disc Proteins in Myopathy and Cardiomyopathy Kirsty Wadmore 1,†, Amar J. Azad 1,† and Katja Gehmlich 1,2,* 1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (K.W.); [email protected] (A.J.A.) 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected]; Tel.: +44-121-414-8259 † These authors contributed equally. Abstract: The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts. -
Pak1 Kinase Controls Cell Shape Through Ribonucleoprotein Granules Joseph O Magliozzi, James B Moseley*
RESEARCH ARTICLE Pak1 kinase controls cell shape through ribonucleoprotein granules Joseph O Magliozzi, James B Moseley* Department of Biochemistry and Cell Biology, The Geisel School of Medicine at Dartmouth, Hanover, United States ABSTRACT Fission yeast cells maintain a rod shape due to conserved signaling pathways that organize the cytoskeleton for polarized growth. We discovered a mechanism linking the conserved protein kinase Pak1 with cell shape through the RNA- binding protein Sts5. Pak1 (also called Shk1 and Orb2) prevents Sts5 association with P bodies by directly phosphorylating its intrinsically disor- dered region (IDR). Pak1 and the cell polarity kinase Orb6 both phosphorylate the Sts5 IDR but at distinct residues. Mutations preventing phosphorylation in the Sts5 IDR cause increased P body formation and defects in cell shape and polarity. Unexpectedly, when cells encounter glucose star- vation, PKA signaling triggers Pak1 recruitment to stress granules with Sts5. Through retargeting experiments, we reveal that Pak1 localizes to stress granules to promote rapid dissolution of Sts5 upon glucose addition. Our work reveals a new role for Pak1 in regulating cell shape through ribonu- cleoprotein granules during normal and stressed growth conditions. Introduction Cell polarity signaling networks determine cell morphology by controlling growth machinery in time and space. Because active growth requires energy, these networks must also respond to changes in the environment such as glucose availability. The p21- activated kinase (PAK) family of protein kinases *For correspondence: are key mediators of cell polarity signaling in many eukaryotes (Hofmann et al., 2004). Following james. b. moseley@ dartmouth. activation by small GTPases like Cdc42, PAKs function in regulating the cytoskeleton and MAPK path- edu ways, and PAK dysregulation is associated with multiple human diseases. -
Evaluation of Mutations in Kras and Braf Genes in Iranian Population with Diffuse Gastric Cancer
WCRJ 2019; 6: e1352 EVALUATION OF MUTATIONS IN KRAS AND BRAF GENES IN IRANIAN POPULATION WITH DIFFUSE GASTRIC CANCER M. SANEIPOUR1,2, A. MORIDNIA3 1Department of Medical Biochemistry, School of Medicine, Shoushtar University of Medical Sciences, Shoushtar, Iran 2Department of Medical Biochemistry, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran 3Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran Abstract – Objective: RAS proteins control signaling pathways which are the main regulators of the normal cell growth and malignant transformation cells. The point mutations in the KRAS gene are current event in numerous human cancers including pancreatic, lung, colon, and breast cancer. BRAF protein is located in the downstream of KRAS and it is revealed to be somatically mutated in various human cancers. KRAS and BRAF mutated genes have a vital role in the estab- lishment and development of tumors. Since there is a little information about BRAF and KRAS mutations in gastric cancer, the present study has been designed. Materials and Methods: We assessed 31 cases that experienced gastrectomy for diffuse gas- tric cancer, according to the histopathological criteria confirmed by pathologist. The patients were hospitalized in the Al-Zahra hospital in the Isfahan province (central Iran) and in the Alaa Cancer Control Center from 2011 to 2016. The DNA sequencing was completed by amplification exon 2 of KRAS and exon 15 of BRAF genes. Results: According to the electropherogram of DNA sequencing we did not find any alterations in the codon 12 and 13 of KRAS and codon 600 of BRAF genes. -
Novel Loss-Of-Function Variants in TRIO Are Associated With
Schultz-Rogers et al. BMC Medical Genetics (2020) 21:219 https://doi.org/10.1186/s12881-020-01159-y CASE REPORT Open Access Novel loss-of-function variants in TRIO are associated with neurodevelopmental disorder: case report Laura Schultz-Rogers1, Karthik Muthusamy2, Filippo Pinto e Vairo1,2, Eric W. Klee1,2 and Brendan Lanpher2* Abstract Background: Damaging variants in TRIO have been associated with moderate to severe neurodevelopmental disorders in humans. While recent work has delineated the positional effect of missense variation on the resulting phenotype, the clinical spectrum associated with loss-of-function variation has yet to be fully defined. Case presentation: We report on two probands with novel loss-of-function variants in TRIO. Patient 1 presents with a severe neurodevelopmental disorder and macrocephaly. The TRIO variant is inherited from his affected mother. Patient 2 presents with moderate developmental delays, microcephaly, and cutis aplasia with a frameshift variant of unknown inheritance. Conclusions: We describe two patients with neurodevelopmental disorder, macro/microcephaly, and cutis aplasia in one patient. Both patients have loss-of-function variants, helping to further characterize how these types of variants affect the phenotypic spectrum associated with TRIO. We also present the third reported case of autosomal dominant inheritance of a damaging variant in TRIO. Keywords: TRIO gene, Autism, Macrocephaly, Microcephaly, Cutis aplasia Background multiple tissue-specific isoforms, including several differ- The human gene TRIO (triple functional domain) en- ent isoforms expressed in the mammalian brain [12–15]. codes a guanine nucleotide exchange factor (GEF) that Studies have shown that expression of TRIO peaks in facilitates the activation of Rho GTPases such as RAC1 the brain in the late prenatal period [16] supporting a [1–3]. -
A Genome-Wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.136192; this version posted June 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Contreras et al., A Genome-wide Library of MADM Mice for Single-Cell Genetic Mosaic Analysis Ximena Contreras1, Amarbayasgalan Davaatseren1, Nicole Amberg1, Andi H. Hansen1, Johanna Sonntag1, Lill Andersen2, Tina Bernthaler2, Anna Heger1, Randy Johnson3, Lindsay A. Schwarz4,5, Liqun Luo4, Thomas Rülicke2 & Simon Hippenmeyer1,6,# 1 Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria 2 Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria 3 Department of Biochemistry and Molecular Biology, University of Texas, Houston, TX 77030, USA 4 HHMI and Department of Biology, Stanford University, Stanford, CA 94305, USA 5 Present address: St. Jude Children’s Research Hospital, Memphis, TN 38105, USA 6 Lead contact #Correspondence and requests for materials should be addressed to S.H. ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.05.136192; this version posted June 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Contreras et al., SUMMARY Mosaic Analysis with Double Markers (MADM) offers a unique approach to visualize and concomitantly manipulate genetically-defined cells in mice with single-cell resolution. -
Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration
Neuron Article Genetic Mosaic Dissection of Lis1 and Ndel1 in Neuronal Migration Simon Hippenmeyer,1,* Yong Ha Youn,2 Hyang Mi Moon,2,3 Kazunari Miyamichi,1 Hui Zong,1,5 Anthony Wynshaw-Boris,2,4 and Liqun Luo1,* 1Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA 2Department of Pediatrics and Institute for Human Genetics 3Biomedical Sciences Graduate Program 4Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco School of Medicine, San Francisco, CA 94143, USA 5Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA *Correspondence: [email protected] (S.H.), [email protected] (L.L.) DOI 10.1016/j.neuron.2010.09.027 SUMMARY studied. Cortical layering occurs in an ‘‘inside-out’’ fashion whereby earlier born neurons occupy deep layers and succes- Coordinated migration of newly born neurons to their sively later born neurons settle in progressively upper layers (An- prospective target laminae is a prerequisite for neural gevine and Sidman, 1961; Rakic, 1974). Upon radial glia progen- circuit assembly in the developing brain. The evolu- itor cell (RGPC)-mediated neurogenesis, newborn migrating tionarily conserved LIS1/NDEL1 complex is essential cortical projection neurons are bipolar-shaped in the ventricular for neuronal migration in the mammalian cerebral zone (VZ) but then convert to a multipolar morphology within the cortex. The cytoplasmic nature of LIS1 and NDEL1 subventricular zone (SVZ) and migrate into the intermediate zone (IZ). A switch from the multipolar state back to a bipolar proteins suggest that they regulate neuronal migra- morphology precedes radial glia-guided locomotion of projec- tion cell autonomously. -
Activation of Aurora-A Is Essential for Neuronal Migration Via Modulation of Microtubule Organization
11050 • The Journal of Neuroscience, August 8, 2012 • 32(32):11050–11066 Cellular/Molecular Activation of Aurora-A Is Essential for Neuronal Migration via Modulation of Microtubule Organization Takako Takitoh,1 Kanako Kumamoto,1 Chen-Chi Wang,2,4 Makoto Sato,2,3,4 Shiori Toba,1 Anthony Wynshaw-Boris,5 and Shinji Hirotsune1 1Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan, 2Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, 3Child Development Research Center, Graduate School of Medical Sciences, University of Fukui, 4Research and Education Program for Life Science, University of Fukui, Fukui 910-1193, Japan, and 5Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, School of Medicine, San Francisco, California 94143 Neuronal migration is a critical feature to ensure proper location and wiring of neurons during cortical development. Postmitotic neurons migrate from the ventricular zone into the cortical plate to establish neuronal lamina in an “inside-out” gradient of maturation. Here, we report that the mitotic kinase Aurora-A is critical for the regulation of microtubule organization during neuronal migration via an Aurora-A–NDEL1 pathway in the mouse. Suppression of Aurora-A activity by inhibitors or siRNA resulted in severe impairment of neuronal migration of granular neurons. In addition, in utero injection of the Aurora-A kinase-dead mutant provoked defective migra- tion of cortical neurons. Furthermore, we demonstrated that suppression of Aurora-A impaired microtubule modulation in migrating neurons. Interestingly, suppression of CDK5 by an inhibitor or siRNA reduced Aurora-A activity and NDEL1 phosphorylation by Aurora-A, which led to defective neuronal migration. -
1714 Gene Comprehensive Cancer Panel Enriched for Clinically Actionable Genes with Additional Biologically Relevant Genes 400-500X Average Coverage on Tumor
xO GENE PANEL 1714 gene comprehensive cancer panel enriched for clinically actionable genes with additional biologically relevant genes 400-500x average coverage on tumor Genes A-C Genes D-F Genes G-I Genes J-L AATK ATAD2B BTG1 CDH7 CREM DACH1 EPHA1 FES G6PC3 HGF IL18RAP JADE1 LMO1 ABCA1 ATF1 BTG2 CDK1 CRHR1 DACH2 EPHA2 FEV G6PD HIF1A IL1R1 JAK1 LMO2 ABCB1 ATM BTG3 CDK10 CRK DAXX EPHA3 FGF1 GAB1 HIF1AN IL1R2 JAK2 LMO7 ABCB11 ATR BTK CDK11A CRKL DBH EPHA4 FGF10 GAB2 HIST1H1E IL1RAP JAK3 LMTK2 ABCB4 ATRX BTRC CDK11B CRLF2 DCC EPHA5 FGF11 GABPA HIST1H3B IL20RA JARID2 LMTK3 ABCC1 AURKA BUB1 CDK12 CRTC1 DCUN1D1 EPHA6 FGF12 GALNT12 HIST1H4E IL20RB JAZF1 LPHN2 ABCC2 AURKB BUB1B CDK13 CRTC2 DCUN1D2 EPHA7 FGF13 GATA1 HLA-A IL21R JMJD1C LPHN3 ABCG1 AURKC BUB3 CDK14 CRTC3 DDB2 EPHA8 FGF14 GATA2 HLA-B IL22RA1 JMJD4 LPP ABCG2 AXIN1 C11orf30 CDK15 CSF1 DDIT3 EPHB1 FGF16 GATA3 HLF IL22RA2 JMJD6 LRP1B ABI1 AXIN2 CACNA1C CDK16 CSF1R DDR1 EPHB2 FGF17 GATA5 HLTF IL23R JMJD7 LRP5 ABL1 AXL CACNA1S CDK17 CSF2RA DDR2 EPHB3 FGF18 GATA6 HMGA1 IL2RA JMJD8 LRP6 ABL2 B2M CACNB2 CDK18 CSF2RB DDX3X EPHB4 FGF19 GDNF HMGA2 IL2RB JUN LRRK2 ACE BABAM1 CADM2 CDK19 CSF3R DDX5 EPHB6 FGF2 GFI1 HMGCR IL2RG JUNB LSM1 ACSL6 BACH1 CALR CDK2 CSK DDX6 EPOR FGF20 GFI1B HNF1A IL3 JUND LTK ACTA2 BACH2 CAMTA1 CDK20 CSNK1D DEK ERBB2 FGF21 GFRA4 HNF1B IL3RA JUP LYL1 ACTC1 BAG4 CAPRIN2 CDK3 CSNK1E DHFR ERBB3 FGF22 GGCX HNRNPA3 IL4R KAT2A LYN ACVR1 BAI3 CARD10 CDK4 CTCF DHH ERBB4 FGF23 GHR HOXA10 IL5RA KAT2B LZTR1 ACVR1B BAP1 CARD11 CDK5 CTCFL DIAPH1 ERCC1 FGF3 GID4 HOXA11 IL6R KAT5 ACVR2A -
A Frustrated Trio
NEWS & VIEWS RESEARCH skin cells in which melanoma arises) are 4. Hodis, E. et al. Cell 150, 251–263 (2012). 8. Jané-Valbuena, J. et al. Cancer Res. 70, 2075–2084 especially sensitive to changes in TERT expres- 5. Krauthammer, M. et al. Nature Genet. 44, (2010). 1006–1014 (2012). 9. Capper, R. et al. Genes Dev. 21, 2495–2508 (2007). sion, because in Horn and colleagues’ study all 6. Harrington, L. Mutat. Res. 730, 37–42 (2012). 10. Xu, L. & Blackburn, E. H. Mol. Cell 28, 315–327 but one person carrying the T-to-G mutation 7. Ding, Z. et al. Cell 148, 896–907 (2012). (2007). developed melanoma, and the unaffected car- rier had multiple naevi. This susceptibility could arise because ETS proteins are targets CONDENSED-MATTER PHYSICS of the MAPK cell-signalling pathway, which is frequently activated in melanoma and benign naevi. In support of this idea, Horn and colleagues found that the TERT-promoter A frustrated trio mutations were found in many of the mela- nomas that had activating BRAF mutations; Geometrical frustration results from an incompatibility between the spatial BRAF is an intermediate in the MAPK path- arrangement of a system’s constituents and the interactions between them. way, and perhaps increased BRAF signalling The effect has now been observed in a triangular triple quantum dot. leads to enhanced activation of ETS factors at the TERT promoter. Another, non-mutually exclusive possibility SABINE ANDERGASSEN interesting situation arises when the system’s is that tissue-specific expression of ETS lattice geometry inhibits the formation of an proteins causes some cell types to become rustration arises when competing ordered, low-temperature spin configuration. -
Characterization of the Tor Kinase Pathway Proteins and Their Possible Roles in the Plant Cell Growth Control
CHARACTERIZATION OF THE TOR KINASE PATHWAY PROTEINS AND THEIR POSSIBLE ROLES IN THE PLANT CELL GROWTH CONTROL DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Magdy M. Mahfouz, Msc. (Molecular Biology) The Ohio State University 2004 Dissertation Committee: Dr. Desh Pal S. Verma, Advisor Dr. Harald Vaessin Dr. Mark Seeger Dr. Iris Meier Approved by _______________________________ Advisor Graduate Program in Molecular Genetics ABSTRACT TOR, target of rapamycin, is an atypical kinase, which controls the regulatory network in yeast and animal cells to regulate their growth in response to environmental cues. In response to nutrients, starvation, and hormones, TOR protein regulates ribosome biogenesis, and translation and transcription of a subset of genes involved in translational machinery (Cutler et al., 2001). It has been shown that TOR modulates translation in eukaryotes by phosphorylation of the downstream effectors and thus regulates the abundance of ribosomes and the translation factors (Dennis et al.1999). Integration of energy levels, nutrient sufficiency and stress information to regulate the translational machinery allows TOR to act as a “master regulator” that strikes a balance between nutrient availability, metabolic processes, protein synthesis, and cell growth (Abraham, 2002). Such a balance is crucial for the cell to ensure its survival. TOR is also at the heart of growth signaling pathways with its substarte AtS6K mediating translational regulation by phosphorylation of ribosomal protein S6 (RPS6;Turck et al., 2004). There is another regulatory role of TOR at the transcriptional level; TOR through its interaction with a phosphatase affects the phosphorylation status of some transcriptional factors and thereby changing their localization from cytoplasm to the nucleus (Cutler et al. -
Forschungsbericht Science Report
FORSCHUNGSBERICHT SCIENCE REPORT2017/2018 ST. ANNA KINDERKREBSFORSCHUNG ST. ANNA CHILDREN’S CANCER RESEARCH INSTITUTE TUMOR BIOLOGY Understanding tumor heterogeneity and relapse in neuroblastoma patients to allow adequate treatment options. MOLECULAR MICROBIOLOGY LCH BIOLOGY Clinically important Targeted resistant mutations in Philadelphia inhibition chromosome-positive leukemias. of the MAPK pathway leads to a STUDIES & STATISTICS rapid and sustained clinical response in severe multisystem LCH. Busulfan and melphalan is considered standard high-dose chemotherapy for high-risk neuroblastoma. GENETICS OF LEUKEMIAS A novel genetic MOLECULAR BIOLOGY OF SOLID TUMORS subtype of leukemia. Understanding mechanisms EPIGENOME-BASED PRECISION MEDICINE of tumor cell plasticity EPIGENETIC and its role in diversity in Ewing sarcoma metastasis. Ewing sarcoma. MORE SCIENCE REPORTS INSIDE >>> [ 06 ] Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute Inhalt Einleitung Vorwort des Institutsleiters 10 Vorwort des wissenschaftlichen Direktors 12 30 Jahre – unseren Spendern sei Dank! 14 Daten & Fakten Kompetitive Drittmittel 2018 20 Zuweisung der Geldmittel 2018 20 Finanzierung 2018 20 Nationen 21 Personelle Zusammensetzung 21 PatientInnenaufkommen im S2IRP 22 2-Jahres-Überlebensrate krebskranker Kinder 23 5-Jahres-Überlebensrate krebskranker Kinder 24 Forschungsnetzwerke 26 Inhalt Forschungsbericht I St. Anna Kinderkrebsforschung | Science Report St. Anna Cancer Research Institute [ 07 ] Science -
Lis1 and Ndel1 Influence the Timing of Nuclear Envelope Breakdown in Neural Stem Cells
University of South Carolina Scholar Commons Faculty Publications Biological Sciences, Department of 9-22-2008 Lis1 and Ndel1 Influence the Timing of Nuclear Envelope Breakdown in Neural Stem Cells Sachin Hebbar University of South Carolina - Columbia Mariano T. Mesngon University of South Carolina - Columbia Aimee M. Guillotte University of South Carolina - Columbia Bhavim Desai University of South Carolina - Columbia, [email protected] Ramses Ayala Mass General Institute for Neurodegenerative Disease See next page for additional authors Follow this and additional works at: https://scholarcommons.sc.edu/biol_facpub Part of the Biology Commons Publication Info The Journal of Cell Biology, Volume 182, Issue 6, 2008, pages 1063-1071. © 2008, the authors. Originally published in the Journal of Cell Biology by the Rockefeller University Press. This Article is brought to you by the Biological Sciences, Department of at Scholar Commons. It has been accepted for inclusion in Faculty Publications by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Author(s) Sachin Hebbar, Mariano T. Mesngon, Aimee M. Guillotte, Bhavim Desai, Ramses Ayala, and Deanna S. Smith This article is available at Scholar Commons: https://scholarcommons.sc.edu/biol_facpub/58 Published September 22, 2008 JCB: REPORT Lis1 and Ndel1 infl uence the timing of nuclear envelope breakdown in neural stem cells Sachin Hebbar , 1 Mariano T. Mesngon , 1 Aimee M. Guillotte , 1 Bhavim Desai , 1 Ramses Ayala , 2 and Deanna S. Smith 1 1 Department of Biological Sciences, University of South Carolina, Columbia, SC 29208 2 Neurology Department, Mass General Institute for Neurodegenerative Disease, Charlestown, MA 02120 is1 and Ndel1 are essential for animal development.