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Adam Barrada, Meriem Djendli, Thierry Desnos, Raphael Mercier, Christophe Robaglia, Marie-Hélène Montané, Benoît Menand
TARGET OF RAPAMYCIN (TOR) is a conserved eukaryotic phosphatidylinositol-3-kinase-related kinase that plays a major role in regulating growth and metabolism in response to environment in plants. We performed a genetic screen for Arabidopsis EMS mutants resistant to the ATP-competitive TOR inhibitor AZD-8055 to identify new components of the plant TOR pathway. We found that loss of function mutants of the DYRK (Dual Specificity Tyrosine Phosphorylation Regulated Kinase) / YAK1 kinase are resistant to AZD-8055 and, reciprocally, that YAK1 overexpressors are hypersensitive...
January 31, 2019: Development
Agnieszka Szamborska-Gbur, Ewelina Rutkowska, Agnieszka Dreas, Michael Frid, Maria Vilenchik, Mariusz Milik, Krzysztof Brzózka, Marcin Król
DYRK1B protein kinase is an emerging anticancer target due to its overexpression in a variety of cancers and its role in cancer chemoresistance through maintaining cancer cells in the G0 (quiescent) state. Consequently, there is a growing interest in the development of potent and selective DYRK1B inhibitors for anticancer therapy. One of the major off-targets is another protein kinase, GSK3β, which phosphorylates an important regulator of cell cycle progression on the same residue as DYRK1B and is involved in multiple signaling pathways...
January 23, 2019: Journal of Molecular Modeling
Stuart T Hamilton, Corina Hutterer, Ece Egilmezer, Mirjam Steingruber, Jens Milbradt, Manfred Marschall, William D Rawlinson
INTRODUCTION: Congenital cytomegalovirus (HCMV) infection may cause significant fetal malformation and in severe cases fetal and neonatal death. Fetal injury may be caused indirectly by the placental response to infection. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) have recently been identified as critical kinases for HCMV replication. In this study we provide first evidence that DYRK1A and DYRK1B are utilised during HCMV placental replication. METHODS: DYRK expression was investigated in AD169- and Merlin-infected TEV-1 trophoblast cells, ex vivo placental explants and naturally infected clinical placentae by immunofluorescence, western blot, co-immunoprecipitation and RT-qPCR...
December 2018: Placenta
Kosei Iwabuchi, Haruna Ohnishi, Kentaro Tamura, Yoichiro Fukao, Tomoaki Furuya, Koro Hattori, Hirokazu Tsukaya, Ikuko Hara-Nishimura
During dark adaptation, plant nuclei move centripetally toward the mid-plane of the leaf blade; thus the nuclei in both the adaxial and abaxial sides become positioned at the inner periclinal walls of cells. This centripetal nuclear positioning implies that a characteristic cell polarity exists within a leaf, but little is known about the mechanism underlying this process. Here we show that ANGUSTIFOLIA (AN) and ACTIN7 regulate centripetal nuclear positioning in Arabidopsis (Arabidopsis thaliana) leaves. Two mutants defective in the positioning of nuclei in the dark were isolated and designated as unusual nuclear positioning 1 (unp1) and unp2...
November 7, 2018: Plant Physiology
Florence Couly, Marine Harari, Carole Dubouilh-Benard, Laetitia Bailly, Emilie Petit, Julien Diharce, Pascal Bonnet, Laurent Meijer, Corinne Fruit, Thierry Besson
Efficient metal catalyzed C⁻H arylation of 8-alkyl-thiazolo[5,4- f ]-quinazolin-9-ones was explored for SAR studies. Application of this powerful chemical tool at the last stage of the synthesis of kinase inhibitors allowed the synthesis of arrays of molecules inspired by fragment-growing studies generated by molecular modeling calculations. Among the potentially active compounds designed through this strategy, FC162 ( 4c ) exhibits nanomolar IC50 values against some kinases, and is the best candidate for the development as a DYRK kinase inhibitor...
August 29, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Chunyan Li, Jinpeng Wang, Kai Song, Jie Meng, Fei Xu, Li Li, Guofan Zhang
BACKGROUND: Both growth and nutritional traits are important economic traits of Crassostrea gigas (C. gigas) in industry. But few work has been done to study the genetic architecture of nutritional traits of the oyster. In this study, we constructed a high-density genetic map of C. gigas to help assemble the genome sequence onto chromosomes, meanwhile explore the genetic basis for nutritional traits via quantitative trait loci (QTL) mapping. RESULTS: The constructed genetic map contained 5024 evenly distributed markers, with an average marker interval of 0...
August 22, 2018: BMC Genomics
Anna Czarna, Jinhua Wang, Diana Zelencova, Yao Liu, Xianming Deng, Hwan Geun Choi, Tinghu Zhang, Wenjun Zhou, Jae Won Chang, Hanne Kildalsen, Ole Morten Seternes, Nathanael S Gray, Richard A Engh, Ulli Rothweiler
DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome critical region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures...
September 13, 2018: Journal of Medicinal Chemistry
Katie L Uhl, Chad R Schultz, Dirk Geerts, André S Bachmann
Background: Neuroblastoma (NB) is an early childhood malignancy that arises from the developing sympathetic nervous system. Harmine is a tricyclic β-carboline alkaloid isolated from the harmal plant that exhibits both cytostatic and cytotoxic effects. Harmine is capable of blocking the activities of dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family proteins and mitogen-activated protein kinase. These kinases promote proliferation and inhibit apoptosis. Methods: Four human NB cell lines were used to study the effects of harmine treatment: SKNBE and KELLY ( MYCN -amplified) as well as SKNAS and SKNFI ( MYCN non-amplified)...
2018: Cancer Cell International
Esti Wahyu Widowati, Simone Bamberg-Lemper, Walter Becker
OBJECTIVE: Dual specificity tyrosine phosphorylation-regulated kinases (DYRK) contain a characteristic sequence motif (DYRK homology box, DH box) that is located N-terminal of the catalytic domain and supports the autophosphorylation of a conserved tyrosine during maturation of the catalytic domain. Two missense mutations in the DH box of human DYRK1B were recently identified as causative of a rare familiar form of metabolic syndrome. We have recently shown that these amino acid exchanges impair maturation of the kinase domain...
May 15, 2018: BMC Research Notes
Esteban J Rozen, Julia Roewenstrunk, María José Barallobre, Chiara Di Vona, Carole Jung, Ana F Figueiredo, Jeroni Luna, Cristina Fillat, Maria L Arbonés, Mariona Graupera, Miguel A Valverde, Susana de la Luna
Angiogenesis is a highly regulated process essential for organ development and maintenance, and its deregulation contributes to inflammation, cardiac disorders, and cancer. The Ca2+ /nuclear factor of activated T cells (NFAT) signaling pathway is central to endothelial cell angiogenic responses, and it is activated by stimuli like vascular endothelial growth factor (VEGF) A. NFAT phosphorylation by dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) is thought to be an inactivating event. Contrary to expectations, we show that the DYRK family member DYRK1A positively regulates VEGF-dependent NFAT transcriptional responses in primary endothelial cells...
May 8, 2018: Cell Reports
Linas J Krulikas, Ian M McDonald, Benjamin Lee, Denis O Okumu, Michael P East, Thomas S K Gilbert, Laura E Herring, Brian T Golitz, Carrow I Wells, Allison D Axtman, William J Zuercher, Timothy M Willson, Dmitri Kireev, Jen Jen Yeh, Gary L Johnson, Antonio T Baines, Lee M Graves
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (MiaS ) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (MiaR ). In an effort to discover kinase inhibitors that inhibited MiaR growth, MiaR cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of MiaR cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor...
September 2018: SLAS Discovery
Anne Walter, Apirat Chaikuad, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases...
2018: PloS One
Rajeev Singh, Matthias Lauth
Hedgehog (Hh)/GLI signaling is an important instructive cue in various processes during embryonic development, such as tissue patterning, stem cell maintenance, and cell differentiation. It also plays crucial roles in the development of many pediatric and adult malignancies. Understanding the molecular mechanisms of pathway regulation is therefore of high interest. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) comprise a group of protein kinases which are emerging modulators of signal transduction, cell proliferation, survival, and cell differentiation...
November 21, 2017: Journal of Developmental Biology
Tzer Chyn Lim, Tomoyuki Hatano, Anton Kamnev, Mohan K Balasubramanian, Ting Gang Chew
The position of the division site dictates the size and fate of daughter cells in many organisms. In animal cells, division-site placement involves overlapping mechanisms, including signaling from the central spindle microtubules, astral microtubules, and spindle poles and through polar contractions [1-3]. In fission yeast, division-site positioning requires overlapping mechanisms involving the anillin-related protein Mid1 and the tip complex (comprising the Kelch-repeat protein Tea1, the Dyrk-kinase Pom1, and the SH3-domain protein Tea4) [4-11]...
March 19, 2018: Current Biology: CB
Mid Eum Lee, Scott F Rusin, Nicole Jenkins, Arminja N Kettenbach, James B Moseley
Connections between the protein kinases that function within complex cell polarity networks are poorly understood. Rod-shaped fission yeast cells grow in a highly polarized manner, and genetic screens have identified many protein kinases, including the CaMKK-like Ssp1 and the MARK/PAR-1 family kinase Kin1, that are required for polarized growth and cell shape, but their functional mechanisms and connections have been unknown [1-5]. We found that Ssp1 promotes cell polarity by phosphorylating the activation loop of Kin1...
January 8, 2018: Current Biology: CB
Hedwig S Kruitwagen, Bart Westendorp, Cornelia S Viebahn, Krista Post, Monique E van Wolferen, Loes A Oosterhoff, David A Egan, Jean-Maurice Delabar, Mathilda J Toussaint, Baukje A Schotanus, Alain de Bruin, Jan Rothuizen, Louis C Penning, Bart Spee
Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay...
January 15, 2018: Stem Cells and Development
Tim Hohmann, Jacqueline Kessler, Urszula Grabiec, Matthias Bache, Dyrk Vordermark, Faramarz Dehghani
Radiation therapy belongs to the most common approaches for cancer therapy leading amongst others to DNA damage like double strand breaks (DSB). DSB can be used as a marker for the effect of radiation on cells. For visualization and assessing the extent of DNA damage the γH2AX foci assay is frequently used. The analysis of the γH2AX foci assay remains complicated as the number of γH2AX foci has to be counted. The quantification is mostly done manually, being time consuming and leading to person-dependent variations...
May 2018: Histology and Histopathology
Nadège Loaëc, Eletta Attanasio, Benoît Villiers, Emilie Durieu, Tania Tahtouh, Morgane Cam, Rohan A Davis, Aline Alencar, Mélanie Roué, Marie-Lise Bourguet-Kondracki, Peter Proksch, Emmanuelle Limanton, Solène Guiheneuf, François Carreaux, Jean-Pierre Bazureau, Michelle Klautau, Laurent Meijer
A large diversity of 2-aminoimidazolone alkaloids is produced by various marine invertebrates, especially by the marine Calcareous sponges Leucetta and Clathrina . The phylogeny of these sponges and the wide scope of 2-aminoimidazolone alkaloids they produce are reviewed in this article. The origin (invertebrate cells, associated microorganisms, or filtered plankton), physiological functions, and natural molecular targets of these alkaloids are largely unknown. Following the identification of leucettamine B as an inhibitor of selected protein kinases, we synthesized a family of analogues, collectively named leucettines, as potent inhibitors of DYRKs (dual-specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) and potential pharmacological leads for the treatment of several diseases, including Alzheimer's disease and Down syndrome...
October 17, 2017: Marine Drugs
Gilberto Pérez-Sánchez, Adriana Jiménez, Marco A Quezada-Ramírez, Enrique Estudillo, Alberto E Ayala-Sarmiento, Guillermo Mendoza-Hernández, Justino Hernández-Soto, Fidel C Hernández-Hernández, Febe E Cázares-Raga, Jose Segovia
GAS1 is a pleiotropic protein that has been investigated because of its ability to induce cell proliferation, cell arrest, and apoptosis, depending on the cellular or the physiological context in which it is expressed. At this point, we have information about the molecular mechanisms by which GAS1 induces proliferation and apoptosis; but very few studies have been focused on elucidating the mechanisms by which GAS1 induces cell arrest. With the aim of expanding our knowledge on this subject, we first focused our research on finding proteins that were preferentially expressed in cells arrested by serum deprivation...
May 2018: Journal of Cellular Physiology
Samira Abu Jhaisha, Esti W Widowati, Isao Kii, Rie Sonamoto, Stefan Knapp, Chrisovalantis Papadopoulos, Walter Becker
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules...
July 25, 2017: Scientific Reports
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