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Chemische Induktion der intrazellulären Signalübertragung

English title Chemical Control of Intracellular Signaling Cascades
Applicant Wymann Matthias
Number 138302
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Genetik Universität Basel
Institution of higher education University of Basel - BS
Main discipline Organic Chemistry
Start/End 01.01.2012 - 31.12.2012
Approved amount 60'000.00
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All Disciplines (3)

Discipline
Organic Chemistry
Biochemistry
Cellular Biology, Cytology

Keywords (4)

Chemical Biology; Protein Translocation; Intracellular chemistry; Covalent Protein Tags

Lay Summary (German)

Lead
Lay summary

Der Status und die Signalstärke von intrazellulären Signalkaskaden bestimmt, ob eine Zelle sich normal verhält und ihre physiologische Rolle im Körper wahrnimmt. Ueberschiessen die Signale, werden Zellen aktiviert, und es kann z.B. zu chronischen Entzündungen oder Krebserkrankungen kommen. Hier sollen neue chemische Werkzeuge zur Untersuchung und sub-zellulären Manipulation von Signalwegen geschaffen werden. Die geplaanten Moleküle sind zellpermeabel und können zwei (oder mehr) Proteine spezifisch und kovalent miteinander verbinden. So können zum Beispiel zytosolische Proteine an bestimmte Membranen oder cytoskeletale Strukturen angedockt werden. Der gewählte Ansatz soll verhindern, dass unspezifische Interaktionen Signalwege beeinträchtigen.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Inhibition of phosphoinositide 3-kinase γ attenuates inflammation, obesity, and cardiovascular risk factors
Wymann MP, Solinas G (2013), Inhibition of phosphoinositide 3-kinase γ attenuates inflammation, obesity, and cardiovascular risk factors, in Annals of the New York Academy of Sciences, 1280(1), 44-47.
Membrane dynamics in physiology and disease
Wymann MP, Simons K (2013), Membrane dynamics in physiology and disease, in FEBS Journal, 280(12), 2729-2729.
Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP
Schmidt C, Schneble N, Müller JP, Bauer R, Perino A, Marone R, Rybalkin SD, Wymann MP, Hirsch E, Wetzker R (2013), Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP, in Neuroscience, 233, 44-53.
Fluid-phase pinocytosis of native low density lipoprotein promotes murine M-CSF differentiated macrophage foam cell formation.
Barthwal Manoj K, Anzinger Joshua J, Xu Qing, Bohnacker Thomas, Wymann Matthias P, Kruth Howard S (2013), Fluid-phase pinocytosis of native low density lipoprotein promotes murine M-CSF differentiated macrophage foam cell formation., in PloS one, 8(3), 58054-58054.
PKCβ Phosphorylates PI3Kγ to Activate It and Release It from GPCR Control.
Walser Romy, Burke John E, Gogvadze Elena, Bohnacker Thomas, Zhang Xuxiao, Hess Daniel, Küenzi Peter, Leitges Michael, Hirsch Emilio, Williams Roger L, Laffargue Muriel, Wymann Matthias P (2013), PKCβ Phosphorylates PI3Kγ to Activate It and Release It from GPCR Control., in PLoS biology, 11(6), 1001587-1001587.
Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy.
Collmann Emilie, Bohnacker Thomas, Marone Romina, Dawson Janet, Rehberg Markus, Stringer Rowan, Krombach Fritz, Burkhart Christoph, Hirsch Emilio, Hollingworth Gregory J, Thomas Matthew, Wymann Matthias P (2013), Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy., in The Journal of allergy and clinical immunology, 0(0), 0-0.
Chemical Development of Intracellular Protein Heterodimerizers
Erhart Dominik, Zimmermann Mirjam, Jacques Olivier, Wittwer Matthias B., Ernst Beat, Constable Edwin, Zvelebil Marketa, Beaufils Florent, Wymann Matthias P. (2013), Chemical Development of Intracellular Protein Heterodimerizers, in CHEMISTRY & BIOLOGY, 20(4), 549-557.
Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP.
Schmidt C, Schneble N, Müller J P, Bauer R, Perino A, Marone R, Rybalkin S D, Wymann M P, Hirsch E, Wetzker R (2013), Phosphoinositide 3-kinase γ mediates microglial phagocytosis via lipid kinase-independent control of cAMP., in Neuroscience, 233, 44-53.
Genetic ablation of PI3Kγ results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels.
Harris Stephanie J, Ciuclan Loredana, Finan Peter M, Wymann Matthias P, Walker Christoph, Westwick John, Ward Stephen G, Thomas Matthew J (2012), Genetic ablation of PI3Kγ results in defective IL-17RA signalling in T lymphocytes and increased IL-17 levels., in European journal of immunology, 42(12), 3394-404.
The chemical biology of phosphoinositide 3-kinases.
Wymann Matthias P, Schultz Carsten (2012), The chemical biology of phosphoinositide 3-kinases., in Chembiochem : a European journal of chemical biology, 13(14), 2022-35.
Key role of PI3Kγ in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration.
Fougerat A, Smirnova N F, Gayral S, Malet N, Hirsch E, Wymann M P, Perret B, Martinez L O, Douillon M, Laffargue M (2012), Key role of PI3Kγ in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration., in British journal of pharmacology, 166(5), 1643-53.
C-C motif chemokine CCL3 and canonical neutrophil attractants promote neutrophil extravasation through common and distinct mechanisms.
Reichel Christoph A, Puhr-Westerheide Daniel, Zuchtriegel Gabriele, Uhl Bernd, Berberich Nina, Zahler Stefan, Wymann Matthias P, Luckow Bruno, Krombach Fritz (2012), C-C motif chemokine CCL3 and canonical neutrophil attractants promote neutrophil extravasation through common and distinct mechanisms., in Blood, 120(4), 880-90.
Luminal decoration of blood vessels by activated perivasal mast cells in allergic rhinitis.
Schaefer T, Zajonz A, Lorentz P, Bohnacker T, Wymann M P, Schweighoffer T (2012), Luminal decoration of blood vessels by activated perivasal mast cells in allergic rhinitis., in Allergy, 67(4), 510-20.
Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3Kγ-dependent fluid-phase pinocytosis of native LDL.
Anzinger Joshua J, Chang Janet, Xu Qing, Barthwal Manoj K, Bohnacker Thomas, Wymann Matthias P, Kruth Howard S (2012), Murine bone marrow-derived macrophages differentiated with GM-CSF become foam cells by PI3Kγ-dependent fluid-phase pinocytosis of native LDL., in Journal of lipid research, 53(1), 34-42.

Collaboration

Group / person Country
Types of collaboration
Peter Spiess, Fachhochschule Nordwestschweiz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Edwin C. Constable, Dept. Chemistry, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
- Industry/business/other use-inspired collaboration
Marketa Zvelebil, ICR, London Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Carsten Schultz, EMBL, Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Berndt Giese, Dept. Chemistry, Fribourg Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
see scrintific report 01.01.2012 global


Associated projects

Number Title Start Funding scheme
126508 Dynamische Protein-Dimerisierung und Membran-Translokation 01.01.2010 Project funding (Div. I-III)
126143 Tracking of Phosphoinositide Pools - A Key Signalling Component in Cancer and Inflammation (EMRC/ECORES/08-EUROMEMBRANE) 01.07.2009 Project funding (special)
126508 Dynamische Protein-Dimerisierung und Membran-Translokation 01.01.2010 Project funding (Div. I-III)
143699 Kovalente Tag Chemie - Intrazelluläre Kontrolle von Receptoren und Signalen 01.01.2013 Project funding (Div. I-III)

Abstract

The status of cellular signaling pathways is crucial to switch from normal physiology to disease. Many signaling cascades are triggered by the relocalization of protein and lipid kinases. Based on a novel prototype molecule, we propose here to establish cell permeable, non-interfering, covalently reacting protein dimerizers and suitable translocation systems. The combination of chemical dimerizers, specifically targeted membrane anchors and tagged signaling enzymes will provide a toolbox to investigate the activation of single signaling nodes at defined cellular localizations.
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