Matthias P Wymann

Universität Basel, Bâle, Basel-City, Switzerland

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Publications (73)685.26 Total impact

  • Toxicology Letters 10/2015; 238(2):S337-S338. DOI:10.1016/j.toxlet.2015.08.963 · 3.26 Impact Factor

  • Cancer Research; 08/2015

  • Cancer Research 08/2015; 75(15 Supplement):4514-4514. DOI:10.1158/1538-7445.AM2015-4514 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2664-2664. DOI:10.1158/1538-7445.AM2015-2664 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):671-671. DOI:10.1158/1538-7445.AM2015-671 · 9.33 Impact Factor
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    ABSTRACT: Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4(+) T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4(+) T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.
    Journal of Experimental Medicine 07/2014; 211(9). DOI:10.1084/jem.20131276 · 12.52 Impact Factor
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    ABSTRACT: Selektive Dimerisierungsreagentien (CIDs; chemical inducers of dimerization) wurden entwickelt, um die Protein-Dimerisierung und -Translokation chemisch zu steuern. Wir stellen hier ein neues, photospaltbares CID (MeNV-HaXS) vor, das HaloTag- und SNAP-tag-Fusionsproteine bindet und eine exzellente Selektivität und intrazelluläre Reaktivität besitzt. Die Anregung bei 360 nm spaltet die Methyl-6-nitroveratryl-Gruppe von MeNV-HaXS, und das “Dimere”, wieder in die beiden Proteine. MeNV-HaXS verknüpft HaloTag- und SNAP-tag-Fusionsproteine und erlaubt ihre zielgerichtete Verschiebung an Membranen und Zellorganellen, z. B. Plasmamembran, Endosomen, Lysosomen, Golgi, Mitochondrien und das Aktin Zytoskeleton. Die photolytische Spaltung von MeNV-HaXS setzt Zielproteine frei und ermöglicht die optische Manipulation der Proteinlokalisation mit hoher subzellulärer Präzision in Raum und Zeit. MeNV-HaXS ermöglicht so kinetische Studien, Manipulation der Proteindynamik und der subzellulärer Enzymaktivität. Demonstriert wurde die Anwendung von MeNV-HaXS für die zielgerichtete Protein-Translokation an den Golgi und die kinetische Erhebung von Importprozessen in den Zellkern.
    Angewandte Chemie 04/2014; 126(18). DOI:10.1002/ange.201310969
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    ABSTRACT: Chemical inducers of dimerization (CIDs) have been developed to orchestrate protein dimerization and translocation. Here we present a novel photocleavable HaloTag- and SNAP-tag-reactive CID (MeNV-HaXS) with excellent selectivity and intracellular reactivity. Excitation at 360 nm cleaves the methyl-6-nitroveratryl core of MeNV-HaXS. MeNV-HaXS covalently links HaloTag- and SNAP-tag fusion proteins, and enables targeting of selected membranes and intracellular organelles. MeNV-HaXS-mediated translocation has been validated for plasma membrane, late endosomes, lysosomes, Golgi, mitochondria, and the actin cytoskeleton. Photocleavage of MeNV-HaXS liberates target proteins and provides access to optical manipulation of protein relocation with high spatiotemporal and subcellular precision. MeNV-HaXS supports kinetic studies of protein dynamics and the manipulation of subcellular enzyme activities, which is exemplified for Golgi-targeted cargo and the assessment of nuclear import kinetics.
    Angewandte Chemie International Edition 04/2014; 53(18). DOI:10.1002/anie.201310969 · 11.26 Impact Factor
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    ABSTRACT: Author Summary Phosphoinositide 3-kinases (PI3Ks) are involved in most essential cellular processes. Class I PI3Ks are heterodimers: class IA PI3Ks are made up of one of a group of regulatory p85-like subunits and one p110α, p110β, or p110δ catalytic p110 subunit, and are activated via binding of their p85 subunit to phosphorylated tyrosine receptors or their substrates. The only, class IB PI3K member, PI3Kγ, operates downstream of G protein-coupled receptors (GPCRs). Recent work suggested that PI3Kγ also operates downstream of IgE-antigen complexes in mast cell activation, but no mechanism was provided. We show that clustering of the high-affinity IgE receptor FcεRI triggers a massive calcium ion influx, which leads to PKCβ activation. In turn, PKCβ phosphorylates Ser582 of the PI3Kγ catalytic p110γ subunit's helical domain. Downstream of GPCRs, p110γ requires a p84 adapter to be functional. Phospho-mimicking mutations at Ser582 disrupt the p84-p110γ interaction, and cellular Ser582 phosphorylation correlates with the loss of p84 from p110γ. Thus our data suggest that PKCβ phosphorylates and activates p110γ downstream of calcium ion influx, while simultaneously disconnecting the phosphorylated p110γ from GPCR signaling. Exploration of the p84-p110γ interaction surface by hydrogen- deuterium exchange mass spectrometry confirmed that the p110γ helical domain forms the main p84-p110γ contact surface. Taken together, the results suggest an unprecedented mechanism of PI3Kγ regulation.
    PLoS Biology 06/2013; 11(6):e1001587. DOI:10.1371/journal.pbio.1001587 · 9.34 Impact Factor
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    ABSTRACT: BACKGROUND: Tissue mast cell numbers are dynamically regulated by recruitment of progenitors from the vasculature. It is unclear whether progenitors are recruited during allergic sensitization and whether recruitment promotes allergic responses. OBJECTIVE: We sought to (1) determine the effect of mast cell recruitment on acute allergic responses and (2) to define the role of phosphoinositide 3-kinase (PI3K) isoforms in sequential steps to allergic responses. METHODS: Gene-targeted mice for PI3Kγ or PI3Kδ or mice treated with isoform-specific PI3K inhibitors (a novel PI3Kγ-specific inhibitor [NVS-PI3-4] and the PI3Kδ inhibitor IC87114) were used to monitor IgE-mediated mast cell recruitment, migration, adhesion by means of intravital microscopy, degranulation, TNF-α release, and subsequent endothelial cell activation in vivo or in bone marrow-derived mast cells. RESULTS: Functional PI3Kγ, but not PI3Kδ, was crucial for mast cell accumulation in IgE-challenged skin, TNF-α release from IgE/antigen-stimulated mast cells, and mast cell/endothelial interactions and chemotaxis. PI3Kγ-deficient bone marrow-derived mast cells did not adhere to the endothelium in TNF-α-treated cremaster muscle, whereas PI3Kδ was not required. Depletion of TNF-α blocked IgE-induced mast cell recruitment, which links tissue mast cell-derived cytokine release to endothelial activation and mast cell recruitment. Interference with mast cell recruitment protected against anaphylaxis and was superior to blockage of tissue mast cell degranulation. CONCLUSIONS: Interference with mast cell recruitment to exacerbated tissues provides a novel strategy to alleviate allergic reactions and surpassed attenuation of tissue mast cell degranulation. This results in prolonged drug action and allows for reduction of drug doses required to block anaphylaxis, an important feature for drugs targeting inflammatory disease in general.
    The Journal of allergy and clinical immunology 05/2013; 132(4). DOI:10.1016/j.jaci.2013.03.008 · 11.48 Impact Factor
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    Matthias P Wymann · Kai Simons ·
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    ABSTRACT: Membranes define the identity of cells: they are crucial for a cell's perception of the environment, they regulate cellular homeostasis, and they function as hubs for extra- and intracellular signals. Countless lipids have been identified, but how they function in different cell organelles is still poorly defined. Dynamic processes such as membrane fusion, fission, aging, and elimination are being delineated, but are not fully understood. We know that localized lipid-protein and lipid-lipid interactions in membranes determine cell function and fate, but much remains to be learned about the exact nature of these processes. This article is protected by copyright. All rights reserved.
    FEBS Journal 05/2013; 280(12). DOI:10.1111/febs.12322 · 4.00 Impact Factor
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    ABSTRACT: Cell activation initiated by receptor ligands or oncogenes triggers complex and convoluted intracellular signaling. Techniques initiating signals at defined starting points and cellular locations are attractive to elucidate the output of selected pathways. Here, we present the development and validation of a protein heterodimerization system based on small molecules cross-linking fusion proteins derived from HaloTags and SNAP-tags. Chemical dimerizers of HaloTag and SNAP-tag (HaXS) show excellent selectivity and have been optimized for intracellular reactivity. HaXS force protein-protein interactions and can translocate proteins to various cellular compartments. Due to the covalent nature of the HaloTag-HaXS-SNAP-tag complex, intracellular dimerization can be easily monitored. First applications include protein targeting to cytoskeleton, to the plasma membrane, to lysosomes, the initiation of the PI3K/mTOR pathway, and multiplexed protein complex formation in combination with the rapamycin dimerization system.
    Chemistry & biology 04/2013; 20(4):549-57. DOI:10.1016/j.chembiol.2013.03.010 · 6.65 Impact Factor
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    ABSTRACT: During atherosclerosis, low-density lipoprotein (LDL)-derived cholesterol accumulates in macrophages to form foam cells. Macrophage uptake of LDL promotes foam cell formation but the mechanism mediating this process is not clear. The present study investigates the mechanism of LDL uptake for macrophage colony-stimulating factor (M-CSF)-differentiated murine bone marrow-derived macrophages. LDL receptor-null (LDLR-/-) macrophages incubated with LDL showed non-saturable accumulation of cholesterol that did not down-regulate for the 24 h examined. Incubation of LDLR-/- macrophages with increasing concentrations of (125)I-LDL showed non-saturable macrophage LDL uptake. A 20-fold excess of unlabeled LDL had no effect on (125)I-LDL uptake by wild-type macrophages and genetic deletion of the macrophage scavenger receptors CD36 and SRA did not affect (125)I-LDL uptake, showing that LDL uptake occurred by fluid-phase pinocytosis independently of receptors. Cholesterol accumulation was inhibited approximately 50% in wild-type and LDLR-/- mice treated with LY294002 or wortmannin, inhibitors of all classes of phosphoinositide 3-kinases (PI3K). Time-lapse, phase-contrast microscopy showed that macropinocytosis, an important fluid-phase uptake pathway in macrophages, was blocked almost completely by PI3K inhibition with wortmannin. Pharmacological inhibition of the class I PI3K isoforms alpha, beta, gamma or delta did not affect macrophage LDL-derived cholesterol accumulation or macropinocytosis. Furthermore, macrophages from mice expressing kinase-dead class I PI3K beta, gamma or delta isoforms showed no decrease in cholesterol accumulation or macropinocytosis when compared with wild-type macrophages. Thus, non-class I PI3K isoforms mediated macropinocytosis in these macrophages. Further characterization of the components necessary for LDL uptake, cholesterol accumulation, and macropinocytosis identified dynamin, microtubules, actin, and vacuolar type H(+)-ATPase as contributing to uptake. However, Pak1, Rac1, and Src-family kinases, which mediate fluid-phase pinocytosis in certain other cell types, were unnecessary. In conclusion, our findings provide evidence that targeting those components mediating macrophage macropinocytosis with inhibitors may be an effective strategy to limit macrophage accumulation of LDL-derived cholesterol in arteries.
    PLoS ONE 03/2013; 8(3):e58054. DOI:10.1371/journal.pone.0058054 · 3.23 Impact Factor
  • Matthias P Wymann · Giovanni Solinas ·
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    ABSTRACT: Phosphoinositide 3-kinase γ (PI3Kγ) plays a central role in inflammation, allergy, cardiovascular, and metabolic disease. Obesity is accompanied by chronic, low-grade inflammation. As PI3Kγ plays a major role in leukocyte recruitment, targeting of PI3Kγ has been considered to be a strategy for attenuating progression of obesity to insulin resistance and type 2 diabetes. Indeed, PI3Kγ null mice are protected from high fat diet-induced obesity, metabolic inflammation, fatty liver, and insulin resistance. The lean phenotype of the PI3Kγ-null mice has been linked to increased thermogenesis and energy expenditure. Surprisingly, the increase in fat mass and metabolic aberrations were not linked to PI3Kγ activity in the hematopoietic compartment. Thermogenesis and oxygen consumption are modulated by PI3Kγ lipid kinase-dependent and -independent signaling mechanisms. PI3Kγ signaling controls metabolic and inflammatory stress, and may provide an entry point for therapeutic strategies in metabolic disease, inflammation, and cardiovascular disease.
    Annals of the New York Academy of Sciences 03/2013; 1280(1):44-7. DOI:10.1111/nyas.12037 · 4.38 Impact Factor
  • Matthias P Wymann · Carsten Schultz ·
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    ABSTRACT: Since its discovery in the late 1980s, phosphoinositide 3-kinase (PI3K), and its isoforms have arguably reached the forefront of signal transduction research. Regulation of this lipid kinase, its functions, its effectors, in short its entire signaling network, has been extensively studied. PI3K inhibitors are frequently used in biochemistry and cell biology. In addition, many pharmaceutical companies have launched drug-discovery programs to identify modulators of PI3Ks. Despite these efforts and a fairly good knowledge of the PI3K signaling network, we still have only a rudimentary picture of the signaling dynamics of PI3K and its lipid products in space and time. It is therefore essential to create and use novel biological and chemical tools to manipulate the phosphoinositide signaling network with spatial and temporal resolution. In this review, we discuss the current and potential future tools that are available and necessary to unravel the various functions of PI3K and its isoforms.
    ChemBioChem 01/2013; 13(14):2022-35. DOI:10.1002/cbic.201200089 · 3.09 Impact Factor
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    ABSTRACT: The signalling molecule PI3Kγ has been reported to play a key role in the immune system and the inflammatory response. In particular, it facilitates the migration of haemato-poietic cells to the site of inflammation. In this study, we reveal a novel role for PI3Kγ in the regulation of the pro-inflammatory cytokine IL-17. Loss of PI3Kγ or expression of a catalytically inactive mutant of PI3Kγ in mice led to increased IL-17 production both in vitro and in vivo in response to various stimuli. The kinetic profile was unaltered from WT cells, with no effect on proliferation or other cytokines. Elevated levels of IL-17 were not due to an aberrant expansion of IL-17-producing cells. Furthermore, we also identified an increase in IL-17RA expression on PI3Kγ(-/-) CD4(+) T cells, yet these cells exhibited impaired PI3K-dependent signalling in response to IL-17A, and subsequent NF-κB phosphorylation. In vivo, instillation of recombinant IL-17 into the airways of mice lacking PI3Kγ signalling also resulted in reduced phosphorylation of Akt. Cell influx in response to IL-17 was also reduced in PI3Kγ(-/-) lungs. These data demonstrate PI3Kγ-dependent signalling downstream of IL-17RA, which plays a pivotal role in regulating IL-17 production in T cells.
    European Journal of Immunology 12/2012; 42(12). DOI:10.1002/eji.201242463 · 4.03 Impact Factor
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    ABSTRACT: Initial observations suggested that C-C motif chemokines exclusively mediate chemotaxis of mononuclear cells. In addition, recent studies also implicated these chemotactic cytokines in the recruitment of neutrophils. The underlying mechanisms remained largely unknown. Using in vivo microscopy on the mouse cremaster muscle, intravascular adherence and subsequent paracellular transmigration of neutrophils elicited by the chemokine (C-C motif) ligand 3 (CCL3, synonym MIP-1α) were significantly diminished in mice with a deficiency of the chemokine (C-C motif) receptor 1 (Ccr1(-/-)) or 5 (Ccr5(-/-)). Using cell-transfer techniques, neutrophil responses required leukocyte CCR1 and nonleukocyte CCR5. Furthermore, neutrophil extravasation elicited by CCL3 was almost completely abolished on inhibition of G protein-receptor coupling and PI3Kγ-dependent signaling, while neutrophil recruitment induced by the canonical neutrophil attractants chemokine (C-X-C motif) ligand 1 (CXCL1, synonym KC) or the lipid mediator platetelet-activating factor (PAF) was only partially reduced. Moreover, Ab blockade of β(2) integrins, of α(4) integrins, or of their putative counter receptors ICAM-1 and VCAM-1 significantly attenuated CCL3-, CXCL1-, or PAF-elicited intravascular adherence and paracellular transmigration of neutrophils. These data indicate that the C-C motif chemokine CCL3 and canonical neutrophil attractants exhibit both common and distinct mechanisms for the regulation of intravascular adherence and transmigration of neutrophils.
    Blood 06/2012; 120(4):880-90. DOI:10.1182/blood-2012-01-402164 · 10.45 Impact Factor
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    ABSTRACT: In allergic diseases, like in rhinitis, antigen challenge induces rapid degranulation of tissue resident mast cells and subsequent recruitment of leukocytes in response to soluble immunmodulators. The fate of mast cell-derived, membrane associated factors in inflamed tissue remained however unresolved. Components of the mast cell granular membrane, including the unique marker CD63var, were examined by FACS and by confocal laser scanning microscopy in cell culture and in diseased human tissue. We discovered that selected mast cell membrane components appeared on the surface of distinct bystander cells. Acceptor cells did not acquire these molecules simply by uptake of soluble material or in the form of exosomes. Instead, physically stable cell-to-cell contact was required for transfer, in which a Notch2-Jagged1 interaction played a decisive role. This process is activation-dependent, unidirectional, and involves a unique membrane topology. Endothelial cells were particularly efficient acceptors. In organotypic 3D in vitro cultures we found that transferred mast cell molecules traversed an endothelial monolayer, and reappeared focally compacted on its distal surface, away from the actual contact zone. Moreover, we observed that such mast cell-derived membrane patches decorate microcapillaries in the nasal mucosa of allergic rhinitis patients. Direct membrane transfer from perivasal mast cells into nearby blood vessels constitutes a novel mechanism to modulate endothelial surface features with apparent significance in allergic diseases.
    Allergy 02/2012; 67(4):510-20. DOI:10.1111/j.1398-9995.2012.02790.x · 6.03 Impact Factor
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    ABSTRACT: Accumulation of cholesterol by macrophage uptake of LDL is a key event in the formation of atherosclerotic plaques. Previous research has shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is present in atherosclerotic plaques and promotes aortic lipid accumulation. However, it has not been determined whether murine GM-CSF-differentiated macrophages take up LDL to become foam cells. GM-CSF-differentiated macrophages from LDL receptor-null mice were incubated with LDL, resulting in massive macrophage cholesterol accumulation. Incubation of LDL receptor-null or wild-type macrophages with increasing concentrations of ¹²⁵I-LDL showed nonsaturable macrophage LDL uptake that was linearly related to the amount of LDL added, indicating that LDL uptake was mediated by fluid-phase pinocytosis. Previous studies suggest that phosphoinositide 3-kinases (PI3K) mediate macrophage fluid-phase pinocytosis, although the isoform mediating this process has not been determined. Because PI3Kγ is known to promote aortic lipid accumulation, we investigated its role in mediating macrophage fluid-phase pinocytosis of LDL. Wild-type macrophages incubated with LDL and the PI3Kγ inhibitor AS605240 or PI3Kγ-null macrophages incubated with LDL showed an ∼50% reduction in LDL uptake and cholesterol accumulation compared with wild-type macrophages incubated with LDL only. These results show that GM-CSF-differentiated murine macrophages become foam cells by fluid-phase pinocytosis of LDL and identify PI3Kγ as contributing to this process.
    The Journal of Lipid Research 11/2011; 53(1):34-42. DOI:10.1194/jlr.M018887 · 4.42 Impact Factor
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    ABSTRACT: Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.
    Proceedings of the National Academy of Sciences 09/2011; 108(42):E854-63. DOI:10.1073/pnas.1106698108 · 9.67 Impact Factor

Publication Stats

6k Citations
685.26 Total Impact Points


  • 2004-2014
    • Universität Basel
      • • Department of Biomedicine
      • • Institut für Biochemie und Genetik
      Bâle, Basel-City, Switzerland
  • 1998-2007
    • Université de Fribourg
      • Department of Medicine
      Freiburg, Fribourg, Switzerland
  • 2005
    • Babraham Institute
      Cambridge, England, United Kingdom