Reinhard Fässler

Mayo Clinic - Rochester, Rochester, Minnesota, United States

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Publications (330)2612.32 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin-mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt-β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β-mediated growth-inhibitory signals and Wnt-β-catenin-mediated growth-promoting signals.
    Nature medicine 03/2014; · 27.14 Impact Factor
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    ABSTRACT: The adhesive interactions of cells with their environment through the integrin family of transmembrane receptors have key roles in regulating multiple aspects of cellular physiology, including cell proliferation, viability, differentiation and migration. Consequently, failure to establish functional cell adhesions, and thus the assembly of associated cytoplasmic scaffolding and signalling networks, can have severe pathological effects. The roles of specific constituents of integrin-mediated adhesions, which are collectively known as the 'integrin adhesome', in diverse pathological states are becoming clear. Indeed, the prominence of mutations in specific adhesome molecules in various human diseases is now appreciated, and experimental as well as in silico approaches provide insights into the molecular mechanisms underlying these pathological conditions.
    Nature Reviews Molecular Cell Biology 03/2014; 15(4):273-88. · 37.16 Impact Factor
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    ABSTRACT: Collagens constitute nearly 30% of all proteins in our body. Type IV collagen is a major and crucial component of basement membranes. Collagen chains undergo several posttranslational modifications that are indispensable for proper collagen function. One of these modifications, prolyl 3-hydroxylation, is accomplished by a family of prolyl 3-hydroxylases (P3H1, P3H2, and P3H3). The present study shows that P3H2-null mice are embryonic-lethal by embryonic day 8.5. The mechanism of the unexpectedly early lethality involves the interaction of non-3-hydroxylated embryonic type IV collagen with the maternal platelet-specific glycoprotein VI (GPVI). This interaction results in maternal platelet aggregation, thrombosis of the maternal blood, and death of the embryo. The phenotype is completely rescued by producing double KOs of P3H2 and GPVI. Double nulls are viable and fertile. Under normal conditions, subendothelial collagens bear the GPVI-binding sites that initiate platelet aggregation upon blood exposure during injuries. In type IV collagen, these sites are normally 3-hydroxylated. Thus, prolyl 3-hydroxylation of type IV collagen has an important function preventing maternal platelet aggregation in response to the early developing embryo. A unique link between blood coagulation and the ECM is established. The newly described mechanism may elucidate some unexplained fetal losses in humans, where thrombosis is often observed at the maternal/fetal interface. Moreover, epigenetic silencing of P3H2 in breast cancers implies that the interaction between GPVI and non-3-hydroxylated type IV collagen might also play a role in the progression of malignant tumors and metastasis.
    Proceedings of the National Academy of Sciences 12/2013; · 9.74 Impact Factor
  • Vaibhao C Janbandhu, Daniel Moik, Reinhard Fässler
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    ABSTRACT: The spatiotemporal manipulations of gene expression by the Cre recombinase (Cre) of bacteriophage P1 has become an essential asset to understanding mammalian genetics. Accumulating evidence suggests that Cre activity can, in addition to excising targeted loxP sites, induce cytotoxic effects, including abnormal cell cycle progression, genomic instability, and apoptosis, which can accelerate cancer progression. It is speculated that these defects are caused by Cre-induced DNA damage at off-target sites. Here we report the formation of tetraploid keratinocytes in the epidermis of keratin 5 and/or keratin 14 promoter-driven Cre (KRT5- and KRT14-Cre) expressing mouse skin. Biochemical analyses and flow cytometry demonstrated that Cre expression also induces DNA damage, genomic instability, and tetraploidy in HCT116 cells, and live-cell imaging revealed an extension of the G 2 cell cycle phase followed by defective or skipping of mitosis as cause for the tetraploidy. Since tetraploidy eventually leads to aneuploidy, a hallmark of cancer, our findings highlight the importance of distinguishing non-specific cytopathic effects from specific Cre/loxP-driven genetic manipulations when using Cre-mediated gene deletions.
    Cell cycle (Georgetown, Tex.) 11/2013; 13(3). · 5.24 Impact Factor
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    ABSTRACT: Increased ligand binding to cellular integrins ("activation") plays important roles in processes such as development, cell migration, extracellular matrix assembly, tumor metastasis, hemostasis, and thrombosis [1-5]. Integrin activation encompasses both increased integrin monomer affinity and increased receptor clustering [6] and depends on integrin-talin interactions [5]. Loss of kindlins results in reduced activation of integrins [7-13]. Kindlins might promote talin binding to integrins through a cooperative mechanism [5, 14-16]; however, kindlins do not increase talin association with integrins [17]. Here, we report that, unlike talin head domain (THD), kindlin-3 has little effect on the affinity of purified monomeric αIIbβ3, and it does not enhance activation by THD. Furthermore, studies with ligands of varying valency show that kindlins primarily increase cellular αIIbβ3 avidity rather than monomer affinity. In platelets or nucleated cells, loss of kindlins markedly reduces αIIbβ3 binding to multivalent but not monovalent ligands. Finally, silencing of kindlins reduces the clustering of ligand-occupied αIIbβ3 as revealed by total internal reflection fluorescence and electron microscopy. Thus, in contrast to talins, kindlins have little primary effect on integrin αIIbβ3 affinity for monovalent ligands and increase multivalent ligand binding by promoting the clustering of talin-activated integrins.
    Current biology: CB 11/2013; · 10.99 Impact Factor
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    ABSTRACT: Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.
    Proceedings of the National Academy of Sciences 10/2013; · 9.74 Impact Factor
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    ABSTRACT: Functional binocular vision requires that inputs arising from the two retinae are integrated and precisely organized within central visual areas. Previous studies have demonstrated an important role for one member of the Ten-m/Odz/teneurin family, Ten-m3, in the mapping of ipsilateral retinal projections. Here, we have identified a distinct role for another closely related family member, Ten-m2, in the formation of the ipsilateral projection in the mouse visual system. Ten-m2 expression was observed in the retina, dorsal lateral geniculate nucleus (dLGN), superior colliculus (SC), and primary visual cortex (V1) of the developing mouse. Anterograde and retrograde tracing experiments in Ten-m2 knock-out (KO) mice revealed a specific decrease in ipsilateral retinal ganglion cells projecting to dLGN and SC. This reduction was most prominent in regions corresponding to ventral retina. No change in the topography of ipsilateral or contralateral projections was observed. While expression of a critical ipsilateral fate determinant, Zic2, appeared unaltered, a notable reduction in one of its downstream targets, EphB1, was observed in ventral retina, suggesting that Ten-m2 may interact with this molecular pathway. Immunohistochemistry for c-fos, a neural activity marker, revealed that the area of V1 driven by ipsilateral inputs was reduced in KOs, while the ratio of ipsilateral-to-contralateral responses contributing to binocular activation during visually evoked potential recordings was also diminished. Finally, a novel two-alternative swim task revealed specific deficits associated with dorsal visual field. These data demonstrate a requirement for Ten-m2 in the establishment of ipsilateral projections, and thus the generation of binocular circuits, critical for mammalian visual function.
    Journal of Neuroscience 07/2013; 33(30):12490-509. · 6.91 Impact Factor
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    ABSTRACT: Integrin-mediated focal adhesions (FAs) are large, multi-protein complexes that link the actin cytoskeleton to the extracellular matrix and take part in adhesion-mediated signaling. These adhesions are highly complex and diverse at the molecular level; thus, assigning particular structural or signaling functions to specific components is highly challenging. Here, we combined functional, structural and biophysical approaches to assess the role of a major FA component, namely, integrin-linked kinase (ILK), in adhesion formation. We show here that ILK plays a key role in the formation of focal complexes, early forms of integrin adhesions, and confirm its involvement in the assembly of fibronectin-bound fibrillar adhesions. Examination of ILK-null fibroblasts by cryo-electron tomography pointed to major structural changes in their FAs, manifested by disarray of the associated actin filaments and an increase in the packing density of FA-related particles (FARPs). Interestingly, adhesion of the mutant cells to the substrate required a higher ligand density than control cells. These data indicate that ILK has a key role in integrin adhesion assembly and sub-structure, and in the regulation of the FA-associated cytoskeleton.
    Journal of Cell Science 07/2013; · 5.88 Impact Factor
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    ABSTRACT: Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.
    The Journal of clinical investigation 07/2013; · 15.39 Impact Factor
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    ABSTRACT: We present a click chemistry-based molecular toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, α5β1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of α5β1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for α5β1, in comparison to control samples, and total selectivity against the binding of the closely related integrin αvβ3. Moreover, our methodology allowed the screening of several phosphonic acid containing anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examined in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the α5β1 integrin. The versatility of our molecular toolkit was proven by shifting the cellular specificity of the materials from α5β1- to αvβ3-expressing fibroblasts by using an αvβ3-selective peptidomimetic as coating molecule. The results shown here represent the first functionalization of Ti-based materials with α5β1- or αvβ3-selective peptidomimetics that allow an unprecedented control to discriminate between α5β1- and αvβ3-mediated adhesions. The role of these two integrins in different biological events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types.
    Chemistry 06/2013; · 5.93 Impact Factor
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    ABSTRACT: How different integrins that bind to the same type of extracellular matrix protein mediate specific functions is unclear. We report the functional analysis of β1- and αv-class integrins expressed in pan-integrin-null fibroblasts seeded on fibronectin. Reconstitution with β1-class integrins promotes myosin-II-independent formation of small peripheral adhesions and cell protrusions, whereas expression of αv-class integrins induces the formation of large focal adhesions. Co-expression of both integrin classes leads to full myosin activation and traction-force development on stiff fibronectin-coated substrates, with αv-class integrins accumulating in adhesion areas exposed to high traction forces. Quantitative proteomics linked αv-class integrins to a GEF-H1-RhoA pathway coupled to the formin mDia1 but not myosin II, and α5β1 integrins to a RhoA-Rock-myosin II pathway. Our study assigns specific functions to distinct fibronectin-binding integrins, demonstrating that α5β1integrins accomplish force generation, whereas αv-class integrins mediate the structural adaptations to forces, which cooperatively enable cells to sense the rigidity of fibronectin-based microenvironments.
    Nature Cell Biology 05/2013; · 20.76 Impact Factor
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    ABSTRACT: β1 integrin adhesion is believed to require binding of talins and kindlins to the membrane proximal and distal NPxY motifs of the β1 cytoplasmic tail, respectively. To test this hypothesis we substituted the membrane proximal and distal tyrosines (Y) of the β1 tail with alanine (A) residues (β1 Y783A; β1 Y795A) in the germline of mice. We report that β1 Y783A or β1 Y795A substitutions blocked talin or kindlin binding, respectively, and led to β1 null-like peri-implantation lethality. Expression of β1 Y783A or β1 Y795A in the epidermis, however, resulted in skin blister and hair follicle phenotypes that were considerably milder than those observed with β1 integrin gene deletion or a β1 double Y-to-A substitution (β1 YY783/795AA). In culture, defects in adhesion, spreading and migration were more severe with the β1 Y783A than with the β1 Y795A substitution despite markedly reduced β1 Y795A integrin surface levels due to diminished protein stability. We conclude that regulation of β1 integrin adhesion through talins and kindlins may differ substantially between stably adherent keratinocytes and cells of the developing embryo and that β1 cytoplasmic NPxY motifs contribute individually and independent of each other to β1 function in keratinocytes.Journal of Investigative Dermatology accepted article preview online, 23 May 2013; doi:10.1038/jid.2013.232.
    Journal of Investigative Dermatology 05/2013; · 6.19 Impact Factor
  • Herbert B Schiller, Reinhard Fässler
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    ABSTRACT: Cells perceive information about the biochemical and biophysical properties of their tissue microenvironment through integrin-mediated cell-matrix adhesions, which connect the cytoskeleton with the extracellular matrix and thereby allow cohesion and long-range mechanical connections within tissues. The formation of cell-matrix adhesions and integrin signalling involves the dynamic recruitment and assembly of an inventory of proteins, collectively termed the 'adhesome', at the adhesive site. The recruitment of some adhesome proteins, most notably the Lin11-, Isl1- and Mec3-domain-containing proteins, depends on mechanical tension generated by myosin II-mediated contractile forces exerted on cell-matrix adhesions. When exposed to force, mechanosensitive adhesome proteins can change their conformation or expose cryptic-binding sites leading to the recruitment of proteins, rearrangement of the cytoskeleton, reinforcement of the adhesive site and signal transduction. Biophysical methods and proteomics revealed force ranges within the adhesome and cytoskeleton, and also force-dependent changes in adhesome composition. In this review, we provide an overview of the compositional dynamics of cell-matrix adhesions, discuss the most prevalent functional domains in adhesome proteins and review literature and concepts about mechanosensing mechanisms that operate at the adhesion site. EMBO reports advance online publication 17 May 2013; doi:10.1038/embor.2013.49.
    EMBO Reports 05/2013; · 7.19 Impact Factor
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    ABSTRACT: Integrin-linked kinase (ILK) localizes to focal adhesions (FAs) where it regulates cell spreading, migration and growth factor receptor signaling. Previous reports showed that overexpressed ILK in which Val386 and Thr387 were substituted with Glycine residues (ILK-VT/GG) could neither interact with Paxillin nor localize to FA in cells expressing endogenous wild-type ILK implying that Paxillin binding to ILK is required for its localization to FAs. Here we show that introducing this mutation into the germline of mice (ILK-VT/GG) caused vasculogenesis defects resulting in a general developmental delay and death at around embryonic day 12.5. Fibroblasts isolated from ILK-VT/GG mice contained mutant ILK in FAs, showed normal adhesion to and spreading on ECM substrates, but displayed impaired migration. Biochemical analysis revealed that VT/GG substitutions decreased ILK protein stability leading to decreased ILK levels, and reduced binding to Paxillin and α-Parvin. Since Paxillin depletion did not affect ILK localization to FAs, the embryonic lethality and the in vitro migration defects are likely due to the reduced levels of ILK-VT/GG and diminished binding to Parvins.
    Journal of Biological Chemistry 05/2013; · 4.65 Impact Factor
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    ABSTRACT: Rationale: Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application despite limited mechanistic understanding of the endogenous response following myocardial infarction (MI). Extracellular matrix (ECM) undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair. Objective: Demonstrate the significance of Fibronectin (Fn), a component of the ECM, for induction of the endogenous CPC response to MI. Methods and Results: This report shows that presence of CPCs correlates with expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery was evident at the end of a 12 week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via β1-Integrin-FAK-Stat3-Pim1 but Akt-independent mechanism. Conclusions: Fn is essential for endogenous CPC expansion and repair needed for stabilization of cardiac function after MI.
    Circulation Research 05/2013; · 11.86 Impact Factor
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    ABSTRACT: Integrin-linked kinase (ILK) is an adaptor protein required to establish and maintain the connection between integrins and the actin cytoskeleton. This linkage is essential for generating force between the extracellular matrix (ECM) and the cell during migration and matrix remodelling. The mechanisms by which ILK stability and turnover are regulated are unknown. Here we report that the E3 ligase CHIP-heat shock protein 90 (Hsp90) axis regulates ILK turnover in fibroblasts. The chaperone Hsp90 stabilizes ILK and facilitates the interaction of ILK with α-parvin. When Hsp90 activity is blocked, ILK is ubiquitinated by CHIP and degraded by the proteasome, resulting in impaired fibroblast migration and a dramatic reduction in the fibrotic response to bleomycin in mice. Together, our results uncover how Hsp90 regulates ILK stability and identify a potential therapeutic strategy to alleviate fibrotic diseases.
    The EMBO Journal 04/2013; · 9.82 Impact Factor
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    ABSTRACT: Cancer progresses through distinct stages, and mouse models recapitulating traits of this progression are frequently used to explore genetic, morphological, and pharmacological aspects of tumor development. To complement genomic investigations of this process, we here quantify phosphoproteomic changes in skin cancer development using the SILAC mouse technology coupled to high-resolution mass spectrometry. We distill protein expression signatures from our data that distinguish between skin cancer stages. A distinct phosphoproteome of the two stages of cancer progression is identified that correlates with perturbed cell growth and implicates cell adhesion as a major driver of malignancy. Importantly, integrated analysis of phosphoproteomic data and prediction of kinase activity revealed PAK4-PKC/SRC network to be highly deregulated in SCC but not in papilloma. This detailed molecular picture, both at the proteome and phosphoproteome level, will prove useful for the study of mechanisms of tumor progression.
    Cell reports. 01/2013;
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    ABSTRACT: Stuck with the right choice: αvβ3- or α5β1-selective integrin ligands were functionalized for surface coating without losing activity and selectivity. The coating of nanostructured gold surfaces with these compounds stimulated subtype-selective cell adhesion of genetically modified αvβ3- or α5β1-expressing fibroblasts in vitro.
    Angewandte Chemie International Edition 01/2013; 52(5):1572-5. · 13.73 Impact Factor
  • Angewandte Chemie 01/2013; 125(5).
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    ABSTRACT: Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P-S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.
    Journal of Experimental Medicine 11/2012; · 13.21 Impact Factor

Publication Stats

15k Citations
2,612.32 Total Impact Points

Institutions

  • 2013
    • Mayo Clinic - Rochester
      • Department of Dermatology
      Rochester, Minnesota, United States
    • Beatson Institute for Cancer Research
      Glasgow, Scotland, United Kingdom
  • 1997–2013
    • Technische Universität München
      • Institute for Advanced Study
      München, Bavaria, Germany
    • University Hospital Regensburg
      • Institut für Pathologie
      Regensburg, Bavaria, Germany
  • 2012
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
    • The University of Manchester
      • Faculty of Life Sciences
      Manchester, England, United Kingdom
  • 1995–2012
    • Max Planck Institute of Biochemistry
      • Department of Molecular Medicine
      München, Bavaria, Germany
    • Austrian Academy of Sciences
      • Institut für Molekulare Biotechnologie (IMBA)
      Vienna, Vienna, Austria
    • University of Alberta
      • Faculty of Pharmacy and Pharmaceutical Sciences
      Edmonton, Alberta, Canada
  • 2011
    • Max Planck Institute for Biology of Ageing
      Köln, North Rhine-Westphalia, Germany
  • 2010
    • SickKids
      Toronto, Ontario, Canada
  • 2009
    • Universität zu Lübeck
      • Department of Dermatology
      Lübeck, Schleswig-Holstein, Germany
    • Vanderbilt University
      • Department of Medicine
      Nashville, MI, United States
  • 2008
    • University of Wuerzburg
      • Rudolf Virchow Center (DFG Research Center for Experimental Biomedicine)
      Würzburg, Bavaria, Germany
    • Wakayama Medical University
      Wakayama, Wakayama, Japan
  • 2007
    • University Joseph Fourier - Grenoble 1
      • Institut Albert Bonniot
      Grenoble, Rhone-Alpes, France
    • University of Sydney
      • School of Medical Sciences
      Sydney, New South Wales, Australia
  • 2005
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 1998–2003
    • Lund University
      Lund, Skåne, Sweden
  • 2001
    • University of Leicester
      • Department of Biochemistry
      Leicester, ENG, United Kingdom
  • 1998–2001
    • University of Wisconsin, Madison
      • Department of Medicine
      Madison, MS, United States
  • 2000
    • Uppsala University
      • Department of Medical Biochemistry and Microbiology
      Uppsala, Uppsala, Sweden
  • 1997–2000
    • University of Cologne
      • • Institute of Biochemistry
      • • Institute of Anatomy I
      Köln, North Rhine-Westphalia, Germany
    • Netherlands Cancer Institute
      Amsterdamo, North Holland, Netherlands
  • 1999
    • Ludwig-Maximilian-University of Munich
      München, Bavaria, Germany
  • 1998–1999
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
  • 1996–1998
    • Uppsala Monitoring Centre
      Uppsala, Uppsala, Sweden