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  1. AU="Gybel', Tomáš"
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  1. Article ; Online: Dual specificity phosphatase 7 drives the formation of cardiac mesoderm in mouse embryonic stem cells.

    Sladeček, Stanislava / Radaszkiewicz, Katarzyna Anna / Bőhmová, Martina / Gybeľ, Tomáš / Radaszkiewicz, Tomasz Witold / Pacherník, Jiří

    PloS one

    2022  Volume 17, Issue 10, Page(s) e0275860

    Abstract: Dual specificity phosphatase 7 (DUSP7) is a protein belonging to a broad group of phosphatases that can dephosphorylate phosphoserine/phosphothreonine as well as phosphotyrosine residues within the same substrate. DUSP7 has been linked to the negative ... ...

    Abstract Dual specificity phosphatase 7 (DUSP7) is a protein belonging to a broad group of phosphatases that can dephosphorylate phosphoserine/phosphothreonine as well as phosphotyrosine residues within the same substrate. DUSP7 has been linked to the negative regulation of mitogen activated protein kinases (MAPK), and in particular to the regulation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). MAPKs play an important role in embryonic development, where their duration, magnitude, and spatiotemporal activity must be strictly controlled by other proteins, among others by DUSPs. In this study, we focused on the effect of DUSP7 depletion on the in vitro differentiation of mouse embryonic stem (ES) cells. We showed that even though DUSP7 knock-out ES cells do retain some of their basic characteristics, when it comes to differentiation, they preferentially differentiate towards neural cells, while the formation of early cardiac mesoderm is repressed. Therefore, our data indicate that DUSP7 is necessary for the correct formation of neuroectoderm and cardiac mesoderm during the in vitro differentiation of ES cells.
    MeSH term(s) Animals ; Dual Specificity Phosphatase 1/metabolism ; Dual-Specificity Phosphatases/genetics ; Dual-Specificity Phosphatases/metabolism ; Mesoderm/metabolism ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Mouse Embryonic Stem Cells/metabolism ; Phosphoserine ; Phosphothreonine ; Phosphotyrosine
    Chemical Substances Phosphothreonine (1114-81-4) ; Phosphoserine (17885-08-4) ; Phosphotyrosine (21820-51-9) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Dual Specificity Phosphatase 1 (EC 3.1.3.48) ; Dual-Specificity Phosphatases (EC 3.1.3.48) ; Dusp7 protein, mouse (EC 3.1.3.48)
    Language English
    Publishing date 2022-10-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0275860
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Discovery of Potent and Exquisitely Selective Inhibitors of Kinase CK1 with Tunable Isoform Selectivity.

    Němec, Václav / Khirsariya, Prashant / Janovská, Pavlína / Moyano, Paula Martín / Maier, Lukáš / Procházková, Petra / Kebková, Pavlína / Gybel', Tomáš / Berger, Benedict-Tilman / Chaikuad, Apirat / Reinecke, Maria / Kuster, Bernhard / Knapp, Stefan / Bryja, Vítězslav / Paruch, Kamil

    Angewandte Chemie (International ed. in English)

    2023  Volume 62, Issue 11, Page(s) e202217532

    Abstract: Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly ... ...

    Abstract Casein kinases 1 (CK1) are key signaling molecules that have emerged recently as attractive therapeutic targets in particular for the treatment of hematological malignancies. Herein, we report the identification of a new class of potent and highly selective inhibitors of CK1α, δ and ϵ. Based on their optimal in vitro and in vivo profiles and their exclusive selectivity, MU1250, MU1500 and MU1742 were selected as quality chemical probes for those CK1 isoforms. At proper concentrations, MU1250 and MU1500 allow for specific targeting of CK1δ or dual inhibition of CK1δ/ϵ in cells. The compound MU1742 also efficiently inhibits CK1α and, to our knowledge, represents the first potent and highly selective inhibitor of this enzyme. In addition, we demonstrate that the central 1H-pyrrolo[2,3-b]pyridine-imidazole pharmacophore can be used as the basis of highly selective inhibitors of other therapeutically relevant protein kinases, e.g. p38α, as exemplified by the compound MU1299.
    MeSH term(s) Casein Kinase I/metabolism ; Protein Isoforms/metabolism ; Protein Kinase Inhibitors/chemistry ; Signal Transduction ; Humans
    Chemical Substances Casein Kinase I (EC 2.7.11.1) ; Protein Isoforms ; Protein Kinase Inhibitors
    Language English
    Publishing date 2023-02-02
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202217532
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The planar cell polarity protein VANG-1/Vangl negatively regulates Wnt/β-catenin signaling through a Dvl dependent mechanism.

    Mentink, Remco A / Rella, Lorenzo / Radaszkiewicz, Tomasz W / Gybel, Tomáš / Betist, Marco C / Bryja, Vitězslav / Korswagen, Hendrik C

    PLoS genetics

    2018  Volume 14, Issue 12, Page(s) e1007840

    Abstract: Van Gogh-like (Vangl) and Prickle (Pk) are core components of the non-canonical Wnt planar cell polarity pathway that controls epithelial polarity and cell migration. Studies in vertebrate model systems have suggested that Vangl and Pk may also inhibit ... ...

    Abstract Van Gogh-like (Vangl) and Prickle (Pk) are core components of the non-canonical Wnt planar cell polarity pathway that controls epithelial polarity and cell migration. Studies in vertebrate model systems have suggested that Vangl and Pk may also inhibit signaling through the canonical Wnt/β-catenin pathway, but the functional significance of this potential cross-talk is unclear. In the nematode C. elegans, the Q neuroblasts and their descendants migrate in opposite directions along the anteroposterior body axis. The direction of these migrations is specified by Wnt signaling, with activation of canonical Wnt signaling driving posterior migration, and non-canonical Wnt signaling anterior migration. Here, we show that the Vangl ortholog VANG-1 influences the Wnt signaling response of the Q neuroblasts by negatively regulating canonical Wnt signaling. This inhibitory activity depends on a carboxy-terminal PDZ binding motif in VANG-1 and the Dishevelled ortholog MIG-5, but is independent of the Pk ortholog PRKL-1. Moreover, using Vangl1 and Vangl2 double mutant cells, we show that a similar mechanism acts in mammalian cells. We conclude that cross-talk between VANG-1/Vangl and the canonical Wnt pathway is an evolutionarily conserved mechanism that ensures robust specification of Wnt signaling responses.
    MeSH term(s) Animals ; Animals, Genetically Modified ; Body Patterning/genetics ; Body Patterning/physiology ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Cell Lineage ; Cell Polarity/genetics ; Cell Polarity/physiology ; Dishevelled Proteins/genetics ; Dishevelled Proteins/metabolism ; Genes, Helminth ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mutation ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Wnt Signaling Pathway/genetics ; Wnt Signaling Pathway/physiology ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances Caenorhabditis elegans Proteins ; Dishevelled Proteins ; Homeodomain Proteins ; Intracellular Signaling Peptides and Proteins ; Mab-5 protein, C elegans ; Mig-5 protein, C elegans ; PRKL-1 protein, C elegans ; Phosphoproteins ; Transcription Factors ; Vang-1 protein, C elegans ; WD repeat containing planar cell polarity effector ; beta Catenin
    Language English
    Publishing date 2018-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2186725-2
    ISSN 1553-7404 ; 1553-7390
    ISSN (online) 1553-7404
    ISSN 1553-7390
    DOI 10.1371/journal.pgen.1007840
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer.

    Kotrbová, Anna / Ovesná, Petra / Gybel', Tomáš / Radaszkiewicz, Tomasz / Bednaříková, Markéta / Hausnerová, Jitka / Jandáková, Eva / Minář, Luboš / Crha, Igor / Weinberger, Vít / Záveský, Luděk / Bryja, Vítězslav / Pospíchalová, Vendula

    Theranostics

    2020  Volume 10, Issue 2, Page(s) 537–552

    Abstract: High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases ... ...

    Abstract High grade serous carcinoma of the ovary, fallopian tube, and peritoneum (HGSC) is the deadliest gynecological disease which results in a five-year survival rate of 30% or less. HGSC is characterized by the early and rapid development of metastases accompanied by a high frequency of ascites
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Ascites/metabolism ; Ascites/pathology ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Female ; Humans ; Middle Aged ; Neoplasm Grading ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/mortality ; Ovarian Neoplasms/pathology ; Survival Rate ; Tumor Microenvironment/physiology ; Wnt Signaling Pathway
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2020-01-01
    Publishing country Australia
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592097-2
    ISSN 1838-7640 ; 1838-7640
    ISSN (online) 1838-7640
    ISSN 1838-7640
    DOI 10.7150/thno.37423
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy.

    Radaszkiewicz, Tomasz / Nosková, Michaela / Gömöryová, Kristína / Vondálová Blanářová, Olga / Radaszkiewicz, Katarzyna Anna / Picková, Markéta / Víchová, Ráchel / Gybeľ, Tomáš / Kaiser, Karol / Demková, Lucia / Kučerová, Lucia / Bárta, Tomáš / Potěšil, David / Zdráhal, Zbyněk / Souček, Karel / Bryja, Vítězslav

    eLife

    2021  Volume 10

    Abstract: RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and ... ...

    Abstract RNF43 is an E3 ubiquitin ligase and known negative regulator of WNT/β-catenin signaling. We demonstrate that RNF43 is also a regulator of noncanonical WNT5A-induced signaling in human cells. Analysis of the RNF43 interactome using BioID and immunoprecipitation showed that RNF43 can interact with the core receptor complex components dedicated to the noncanonical Wnt pathway such as ROR1, ROR2, VANGL1, and VANGL2. RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation. These activities of RNF43 are physiologically relevant and block pro-metastatic WNT5A signaling in melanoma. RNF43 inhibits responses to WNT5A, which results in the suppression of invasive properties of melanoma cells. Furthermore, RNF43 prevented WNT5A-assisted development of resistance to BRAF V600E and MEK inhibitors. Next, RNF43 acted as melanoma suppressor and improved response to targeted therapies in vivo. In line with these findings,
    MeSH term(s) Animals ; Male ; Melanoma/genetics ; Melanoma/pathology ; Melanoma/prevention & control ; Mice ; Mice, Inbred NOD ; Neoplasm Invasiveness/genetics ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Wnt-5a Protein/genetics ; Wnt-5a Protein/metabolism
    Chemical Substances WNT5A protein, human ; Wnt-5a Protein ; RNF43 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2021-10-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.65759
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization.

    Strakova, Katerina / Kowalski-Jahn, Maria / Gybel, Tomas / Valnohova, Jana / Dhople, Vishnu M / Harnos, Jakub / Bernatik, Ondrej / Ganji, Ranjani Sri / Zdrahal, Zbynek / Mulder, Jan / Lindskog, Cecilia / Bryja, Vitezslav / Schulte, Gunnar

    The Journal of biological chemistry

    2018  Volume 293, Issue 48, Page(s) 18477–18493

    Abstract: Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be ... ...

    Abstract Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD
    MeSH term(s) Amino Acid Sequence ; Antibodies/immunology ; Casein Kinase I/metabolism ; Cell Membrane/metabolism ; Dishevelled Proteins/chemistry ; Dishevelled Proteins/physiology ; Epithelium/metabolism ; Fallopian Tubes/metabolism ; Female ; Frizzled Receptors/chemistry ; Frizzled Receptors/metabolism ; HEK293 Cells ; Humans ; Mass Spectrometry ; Phosphoproteins/immunology ; Phosphorylation ; Serine/metabolism ; Signal Transduction
    Chemical Substances Antibodies ; Dishevelled Proteins ; FZD6 protein, human ; Frizzled Receptors ; Phosphoproteins ; Serine (452VLY9402) ; Casein Kinase I (EC 2.7.11.1)
    Language English
    Publishing date 2018-10-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA118.004656
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1.

    Harnoš, Jakub / Cañizal, Maria Consuelo Alonso / Jurásek, Miroslav / Kumar, Jitender / Holler, Cornelia / Schambony, Alexandra / Hanáková, Kateřina / Bernatík, Ondřej / Zdráhal, Zbyněk / Gömöryová, Kristína / Gybeľ, Tomáš / Radaszkiewicz, Tomasz Witold / Kravec, Marek / Trantírek, Lukáš / Ryneš, Jan / Dave, Zankruti / Fernández-Llamazares, Ana Iris / Vácha, Robert / Tripsianes, Konstantinos /
    Hoffmann, Carsten / Bryja, Vítězslav

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 1804

    Abstract: Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo ... ...

    Abstract Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.
    MeSH term(s) Animals ; Biosensing Techniques ; Casein Kinase Iepsilon/genetics ; Casein Kinase Iepsilon/metabolism ; Dishevelled Proteins/genetics ; Dishevelled Proteins/metabolism ; Enzyme Assays/methods ; Fluorescence Resonance Energy Transfer ; Frizzled Receptors/metabolism ; Gene Knockout Techniques ; HEK293 Cells ; Humans ; Microscopy, Fluorescence/methods ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Oocytes ; PDZ Domains/physiology ; Phosphorylation/physiology ; Single-Cell Analysis/methods ; Wnt Signaling Pathway/physiology ; Xenopus laevis
    Chemical Substances DVL3 protein, human ; Dishevelled Proteins ; FZD6 protein, human ; Frizzled Receptors ; Casein Kinase Iepsilon (EC 2.7.11.1)
    Language English
    Publishing date 2019-04-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-09651-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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