Stephan M Feller

Martin Luther University Halle-Wittenberg, Halle-on-the-Saale, Saxony-Anhalt, Germany

Are you Stephan M Feller?

Claim your profile

Publications (105)538.1 Total impact

  • Article: ID: 79

    Cytokine 11/2015; 76(1):80. DOI:10.1016/j.cyto.2015.08.109 · 2.66 Impact Factor
  • Article: ID: 58

    Cytokine 11/2015; 76(1):75. DOI:10.1016/j.cyto.2015.08.088 · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD2AP is an adaptor protein involved in membrane trafficking, with essential roles in maintaining podocyte function within the kidney glomerulus. CD2AP contains three SH3 domains that mediate multiple protein-protein interactions. However, a detailed comparison of the molecular binding preferences of each SH3 remained unexplored, as well as the discovery of novel interactors. Thus, we studied the binding properties of each SH3 domain to the known interactor Casitas B-lineage lymphoma protein (c-CBL), conducted a peptide-array screen based on the recognition motif P-x-P-x-P-R, and identified 40 known or novel candidate binding proteins, such as RIN3, a RAB5-activating guanine-nucleotide exchange factor (GEF). CD2AP SH3 domains 1 and 2 generally bound with similar characteristics and specificities, whereas the SH3-3 domain bound more weakly to most peptide ligands tested, yet recognized an unusually extended sequence in ALG-2-interacting protein X (ALIX). RIN3 peptide scanning arrays revealed two CD2AP binding sites, recognized by all three SH3 domains, but SH3-3 appeared non-functional in precipitation experiments. RIN3 recruited CD2AP to RAB5a-positive early endosomes via these interaction sites. Permutation arrays and isothermal titration calorimetry (ITC) data show that the preferred binding motif is P-x-P/A-x-p-R. Two high-resolution crystal structures (1.65 @Aring; and 1.11 @Aring;) of CD2AP SH3-1 and SH3-2 solved in complex with RIN3 epitopes 1 and 2, respectively, indicated that another extended motif is relevant in epitope 2. In conclusion, we have discovered novel interaction candidates for CD2AP and characterized subtle yet significant differences in the recognition preferences of its three SH3 domains to c-CBL, ALIX and RIN3. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 08/2015; 290(42). DOI:10.1074/jbc.M115.637207 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: THEMIS is critical for conventional T-cell development, but its precise molecular function remains elusive. Here, we show that THEMIS constitutively associates with the phosphatases SHP1 and SHP2. This complex requires the adapter GRB2, which bridges SHP to THEMIS in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Consistent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knock-down increased TCR-induced CD3-ζ phosphorylation, Erk activation and CD69 expression, but not LCK phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP1 knock-down. Remarkably, a KI mutation of LCK Ser59, previously suggested to be key in ERK-mediated resistance towards SHP1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, the THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favours T-cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T-cell development and differentiation. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.
    The EMBO Journal 12/2014; 34(3). DOI:10.15252/embj.201387725 · 10.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The timely orchestration of multiple signalling pathways is crucial for the integrity of an organism and therefore tightly controlled. Gab family proteins coordinate signal transduction at the plasma membrane (PM) by acting as docking platforms for signalling components involved in MAP kinase (MAPK), PI3 kinase (PI3K), phospholipase C (PLC) and Rho family GTPase signalling. The interaction with these components as well as the targeting of the docking platform to the PM underlie complex spatial and temporal regulatory mechanisms. Deregulated Gab1 activation and membrane binding has been observed in some haematopoietic malignancies and solid tumours, thereby contributing, for example, to the development of Philadelphia chromosome-negative myeloproliferative neoplasms and certain lung cancers. Previously, we could demonstrate that the presence of PIP3 in the PM, which is increased in many cancer cells, is not sufficient for constitutive Gab1 membrane recruitment. In addition, MAPK-dependent phosphorylation of Gab1 at serine 552 (Ser552) is vital for Gab1 membrane binding. Here, we confirm our hypothesis that in the absence of MAPK activity an intrinsic part of Gab1 prevents binding to PIP3 at the PM. This epitope of Gab1, which encompasses Ser552, interacts directly with the Gab1 PH domain. Two arginines located in positions +4 and +8 of Ser552 are essential for the interaction with the PH domain, as well as for the inhibition of membrane recruitment of unphosphorylated Gab1. Ser552 phosphorylation is dispensable in respective arginine to alanine mutants of Gab1. Gab1 recruitment to the PM is highly dynamic and continuous PI3K and MAPK activities are both essential for sustained Gab1 membrane localisation. Our data document the existence of a sophisticated and robust control mechanism that prevents Gab1 translocation and signalling complex assembly after the activation of either MAPK or PI3K alone. Copyright © 2014. Published by Elsevier Inc.
    Cellular Signalling 11/2014; 27(2). DOI:10.1016/j.cellsig.2014.11.017 · 4.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Helicobacter pylori is associated with inflammatory diseases and can cause gastric cancer and mucosa-associated lymphoma. One of the bacterium's key proteins is high temperature requirement A (HpHtrA) protein, an extracellular serine protease that cleaves E-cadherin of gastric epithelial cells, which leads to loss of cell-cell adhesion. Inhibition of HpHtrA may constitute an intervention strategy against H. pylori infection. Guided by the computational prediction of hypothetical ligand binding sites on the surface of HpHtrA, we performed residue mutation experiments that confirmed the functional relevance of an allosteric region. We virtually screened for potential ligands addressing this surface cleft located between the catalytic and PDZ1 domains. Our receptor-based computational method represents protein surface pockets in terms of graph frameworks and retrieves small molecules that satisfy the constraints given by the pocket framework. A new chemical entity was identified that blocked E-cadherin cleavage in vitro by direct binding to HpHtrA, and efficiently blocked pathogen transmigration across the gastric epithelial barrier. A preliminary crystal structure of HpHtrA confirms the validity of a comparative “homology” model of the enzyme, which we used for the computational study. The results of this study demonstrate that addressing orphan protein surface cavities of target macromolecules can lead to new bioactive ligands.
    Chemical Science 06/2014; 5(9). DOI:10.1039/C4SC01443J · 9.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a growing interest in understanding the properties of intrinsically disordered proteins (IDPs); however, the characterization of these states remains an open challenge. IDPs appear to have functional roles that diverge from those of folded proteins and revolve around their ability to act as hubs for protein-protein interactions. To gain a better understanding of the modes of binding of IDPs, we combined statistical mechanics, calorimetry, and NMR spectroscopy to investigate the recognition and binding of a fragment from the disordered protein Gab2 by the growth factor receptor-bound protein 2 (Grb2), a key interaction for normal cell signaling and cancer development. Structural ensemble refinement by NMR chemical shifts, thermodynamics measurements, and analysis of point mutations indicated that the population of preexisting bound conformations in the free-state ensemble of Gab2 is an essential determinant for recognition and binding by Grb2. A key role was found for transient polyproline II (PPII) structures and extended conformations. Our findings are likely to have very general implications for the biological behavior of IDPs in light of the evidence that a large fraction of these proteins possess a specific propensity to form PPII and to adopt conformations that are more extended than the typical random-coil states.
    Biophysical Journal 04/2014; 106(8):1771-9. DOI:10.1016/j.bpj.2014.03.004 · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The lysyl oxidase gene inhibits Ras signaling in transformed fibroblasts and breast cancer cells. Its activity was mapped to the 162 amino acid propeptide domain (LOX-PP) of the lysyl oxidase precursor protein. LOX-PP inhibited the Her-2/Ras signaling axis in breast cancer cells, and reduced the Her-2-driven breast tumor burden in a xenograft model. Since its mechanism of action is largely unknown, co-affinity-purification/mass spectrometry was performed and the "Cbl-interacting protein of 85-kDa" (CIN85) identified as an associating protein. CIN85 is an SH3-containing adapter protein that is overexpressed in invasive breast cancers. The CIN85 SH3 domains interact with c-Cbl, an E3 ubiquitin ligase, via an unconventional PxxxPR ligand sequence, with the highest affinity displayed by the SH3-B domain. Interaction with CIN85 recruits c-Cbl to the AMAP1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix. Direct interaction of LOX-PP with CIN85 was confirmed using co-immunoprecipitation analysis of lysates from breast cancer cells and of purified expressed proteins. CIN85 interaction with c-Cbl was reduced by LOX-PP. Domain specific CIN85 regions and deletion mutants of LOX-PP were prepared and used to map the sites of interaction to the SH3-B domain of CIN85 and to an epitope encompassing amino acids 111 to 116 of LOX-PP. Specific LOX-PP point mutant proteins P111A and R116A failed to interact with CIN85 or to compete for CIN85 binding with c-Cbl. Structural modeling identified a new atypical PxpxxRh SH3-binding motif in this region of LOX-PP. The LOX-PP interaction with CIN85 was shown to reduce the invasive phenotype of breast cancer cells, including their ability to degrade the surrounding extracellular matrix and for Matrigel outgrowth. Thus, LOX-PP interacts with CIN85 via a novel SH3-binding motif and this association reduces CIN85-promoted invasion by breast cancer cells.
    PLoS ONE 10/2013; 8(10):e77288. DOI:10.1371/journal.pone.0077288 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Up-regulation of p63 expression is required for ASPP2(Δexon3/+) BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB-mediated repression of p63.
    Proceedings of the National Academy of Sciences 10/2013; 110(44). DOI:10.1073/pnas.1309362110 · 9.67 Impact Factor
  • Source
    Stephan M Feller ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Tony was widely recognized as a world leader in the field of signal transduction and conducted seminal work especially on signaling processes related to protein -- protein interactions and cancers. He will be much missed by many colleagues around the world.
    Cell Communication and Signaling 08/2013; 11(1):61. DOI:10.1186/1478-811X-11-61 · 3.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks. We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct alphaII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and beta-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, beta-actin networks were disturbed and the integrity of Z- and intercalated discs was markedly impaired. Together, our data suggest that Mena, VASP, and alphaII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disturbed beta-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
    Cell Communication and Signaling 08/2013; 11(1):56. DOI:10.1186/1478-811X-11-56 · 3.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Colorectal cancer (CRC) is a major contributor to cancer mortality and morbidity. LIM kinase 2 (LIMK2) promotes tumour cell invasion and metastasis. The objectives of this study were to determine how LIMK2 expression is associated with CRC progression and patient outcome, and to use genetically modified Drosophila and mice to determine how LIMK2 deletion affects gastrointestinal stem cell regulation and tumour development. Design LIMK2 expression and activity were measured by immunostaining tumours from CRC-prone mice, human CRC cell lines and 650 human tumours. LIMK knockdown in Drosophila or Limk2 deletion in mice allowed for assessment of their contributions to gastrointestinal stem cell homeostasis and tumour development. Results LIMK2 expression was reduced in intestinal tumours of cancer-prone mice, as well as in human CRC cell lines and tumours. Reduced LIMK2 expression and substrate phosphorylation were associated with shorter patient survival. Genetic analysis in Drosophila midgut and intestinal epithelial cells isolated from genetically modified mice revealed a conserved role for LIMK2 in constraining gastrointestinal stem cell proliferation. Limk2 deletion increased colon tumour size in a colitis-associated colorectal mouse cancer model. Conclusions This study revealed that LIMK2 expression and activity progressively decrease with advancing stage, and supports the hypothesis that there is selective pressure for reduced LIMK2 expression in CRC to relieve negative constraints imposed upon gastrointestinal stem cells.
    Gut 04/2013; 63(3). DOI:10.1136/gutjnl-2012-303883 · 14.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thymocyte-expressed molecule involved in selection (THEMIS) is a recently identified regulator of thymocyte positive selection. THEMIS's mechanism of action is unknown, and whether it has a role in TCR-proximal signaling is controversial. In this article, we show that THEMIS and the adapter molecule growth factor receptor-bound protein 2 (GRB2) associate constitutively through binding of a conserved PxRPxK motif within the proline-rich region 1 of THEMIS to the C-terminal SH3-domain of GRB2. This association is indispensable for THEMIS recruitment to the immunological synapse via the transmembrane adapter linker for activation of T cells (LAT) and for THEMIS phosphorylation by Lck and ZAP-70. Two major sites of tyrosine phosphorylation were mapped to a YY-motif close to proline-rich region 1. The YY-motif was crucial for GRB2 binding, suggesting that this region of THEMIS might control local phosphorylation-dependent conformational changes important for THEMIS function. Finally, THEMIS binding to GRB2 was required for thymocyte development. Our data firmly assign THEMIS to the TCR-proximal signaling cascade as a participant in the LAT signalosome and suggest that the THEMIS-GRB2 complex might be involved in shaping the nature of Ras signaling, thereby governing thymic selection.
    The Journal of Immunology 03/2013; 190(7). DOI:10.4049/jimmunol.1203389 · 4.92 Impact Factor
  • Source
    Stephan M Feller ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The newly installed Life Sciences Breakthrough Prize (, which comes with more than double the financial reward of the Nobel Prize, has been awarded to several world-leaders in the field of cancer-related cell signaling and therapy research: Lewis C. Cantley (PI3 kinase), Hans Clevers (Wnt signaling), Charles L. Sawyers (signaling-targeted cancer therapy), Bert Vogelstein (colorectal cancer signaling) and Robert Weinberg (Ras & other cancer-relevant genes). They have all made remarkable contributions to our understanding of cell communication and malignancies over the last decades. Needless to say that virtually all other awardees of the 11 scientists honored in 2013 have also, in one way or another, touched upon signaling molecules, highlighting the fundamental interdisciplinarity and significance of signal transduction for living cells in general. For example, Shinya Yamanaka's exciting work was built on the four transcriptional signaling proteins, Oct3/4, Sox2, Klf4 and c-Myc.
    Cell Communication and Signaling 03/2013; 11(1):17. DOI:10.1186/1478-811X-11-17 · 3.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We comparatively analyzed the basal activity of extra-cellular signal-regulated kinase (Erk1/2) in lysates of 10 human colorectal cancer cell lines by semi-quantitative Western blotting and time-resolved NMR spectroscopy. Both methods revealed heterogeneous levels of endogenous Erk1/2 activities in a highly consistent manner. Upon treatment with U0126, an inhibitor of mitogen-activated protein kinase kinase (MEK) acting upstream of Erk1/2, Western-blotting and NMR congruently reported specific modulations of cellular phospho-Erk levels that translated into reduced kinase activities. Results obtained in this study highlight the complementary nature of antibody- and NMR-based phospho-detection techniques. They further exemplify the usefulness of time-resolved NMR measurements in providing fast and quantitative readouts of kinase activities and kinase inhibitor efficacies in native cellular environments.
    Biochimica et Biophysica Acta 01/2013; 1834(7). DOI:10.1016/j.bbapap.2013.01.023 · 4.66 Impact Factor
  • Source
    Stephan Feller ·
    [Show abstract] [Hide abstract]
    ABSTRACT: With iPS cells, sncRNAs, chromatin modification regulation and cancer stem cells already cooling off again, i.e. not being guaranteed publications in the 'ultimate' journals anymore, what will be very soon the new red-hot (or super-cool, i.e. anything but lukewarm) 'kid on the block'? We would vote for microproteins. In case you do not know what they are, no need to worry: nobody does.
    Cell Communication and Signaling 12/2012; 10(1):42. DOI:10.1186/1478-811X-10-42 · 3.38 Impact Factor
  • Source
    Tomonori Kaneko · Rakesh Joshi · Stephan M Feller · Shawn S C Li ·
    [Show abstract] [Hide abstract]
    ABSTRACT: SH2 domains are long known prominent players in the field of phosphotyrosine recognition within signaling protein networks. However, over the years they have been joined by an increasing number of other protein domain families that can, at least with some of their members, also recognise pTyr residues in a sequence-specific context. This superfamily of pTyr recognition modules, which includes substantial fractions of the PTB domains, as well as much smaller, or even single member fractions like the HYB domain, the PKCdelta and PKCtheta C2 domains and RKIP, represents a fascinating, medically relevant and hence intensely studied part of the cellular signaling architecture of metazoans. Protein tyrosine phosphorylation clearly serves a plethora of functions and pTyr recognition domains are used in a similarly wide range of interaction modes, which encompass, for example, partner protein switching, tandem recognition functionalities and the interaction with catalytically active protein domains. If looked upon closely enough, virtually no pTyr recognition and regulation event is an exact mirror image of another one in the same cell. Thus, the more we learn about the biology and ultrastructural details of pTyr recognition domains, the more does it become apparent that nature cleverly combines and varies a few basic principles to generate a sheer endless number of sophisticated and highly effective recognition/regulation events that are, under normal conditions, elegantly orchestrated in time and space. This knowledge is also valuable when exploring pTyr reader domains as diagnostic tools, drug targets or therapeutic reagents to combat human diseases.
    Cell Communication and Signaling 11/2012; 10(1):32. DOI:10.1186/1478-811X-10-32 · 3.38 Impact Factor
  • Source
    Stephan M Feller · Marc Lewitzky ·
    [Show abstract] [Hide abstract]
    ABSTRACT: DNAs and proteins are major classes of biomolecules that differ in many aspects. However, a considerable number of their members also share a common architectural feature that enables the assembly of multi-protein complexes and thereby permits the effective processing of signals: loop structures of substantial sizes. Here we briefly review a few representative examples and suggest a functional classification of different types of loop structures. In proteins, these loops occur in protein regions classified as intrinsically disordered. Studying such loops, their binders and their interactions with other loops should reveal much about cellular information computation and signaling network architectures. It is also expected to provide critical information for synthetic biologists and bioengineers.
    Cell Communication and Signaling 10/2012; 10(1). DOI:10.1186/1478-811X-10-31 · 3.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3(10) helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC(50) 320μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.
    Bioorganic & medicinal chemistry 10/2012; 21(14). DOI:10.1016/j.bmc.2012.10.023 · 2.79 Impact Factor
  • Source
    Stephan M Feller ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Can trustworthy science flourish in countries suffering from dictatorship? This is an increasingly relevant question. Many commercial publishers want to maximise their profits (as is to be expected in a capitalistic system) and are pushing into non-democratic countries with rapid economic growth like China. But how much can we trust the papers coming from countries with dictatorial regimes?
    Cell Communication and Signaling 08/2012; 10(1):24. DOI:10.1186/1478-811X-10-24 · 3.38 Impact Factor

Publication Stats

3k Citations
538.10 Total Impact Points


  • 2013-2015
    • Martin Luther University Halle-Wittenberg
      • Institute for Molecular Medicine
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 2001-2014
    • University of Oxford
      • • Department of Oncology
      • • Molecular Oncology Research Group
      • • Weatherall Institute of Molecular Medicine
      • • Cancer Research Group
      Oxford, England, United Kingdom
    • University of Lausanne
      Lausanne, Vaud, Switzerland
  • 2002-2012
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 2010
    • University of Helsinki
      • Department of Virology
      Helsinki, Southern Finland Province, Finland
  • 2009
    • RWTH Aachen University
      • Institute of Biochemistry and Molecular Biology
      Aachen, North Rhine-Westphalia, Germany
  • 2007-2009
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2004
    • University of Burgundy
      Dijon, Bourgogne, France
  • 1998-2002
    • University of Wuerzburg
      • Institute for Medical Radiation and Cell Research
      Würzburg, Bavaria, Germany
  • 2000
    • Technische Universität München
      München, Bavaria, Germany
  • 1995
    • The Rockefeller University
      New York, New York, United States
  • 1992
    • Robert Wood Johnson University Hospital
      Нью-Брансуик, New Jersey, United States