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  • 1.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Bachar, Moshe
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Conti, Mary-Anne
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Adelstein, Robert S.
    Laboratory of Molecular Cardiology, the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, Maryland.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Ivanov, Andrei I.
    Epithelial Pathobiology Research Unit, the Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Gastroenterology and Hepatology Division, Department of Medicine, The University of Rochester, Rochester New York.
    Non-muscle myosin IIA differentially regulates intestinal epithelial cell restitution and matrix invasion2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 2, p. 436-448Article in journal (Refereed)
    Abstract [en]

    Epithelial cell motility is critical for self-rejuvenation of normal intestinal mucosa, wound repair, and cancer metastasis. This process is regulated by the reorganization of the F-actin cytoskeleton, which is driven by a myosin II motor. However, the role of myosin II in regulating epithelial cell migration remains poorly understood. This study addressed the role of non-muscle myosin (NM) IIA in two different modes of epithelial cell migration: two-dimensional (2-D) migration that occurs during wound closure and three-dimensional (3-D) migration through a Matrigel matrix that occurs during cancer metastasis. Pharmacological inhibition or siRNA-mediated knockdown of NM IIA in SK-CO15 human colonic epithelial cells resulted in decreased 2-D migration and increased 3-D invasion. The attenuated 2-D migration was associated with increased cell adhesiveness to collagen and laminin and enhanced expression of beta1-integrin and paxillin. On the 2-D surface, NM IIA-deficient SK-CO15 cells failed to assemble focal adhesions and F-actin stress fibers. In contrast, the enhanced invasion of NM IIA-depleted cells was dependent on Raf-ERK1/2 signaling pathway activation, enhanced calpain activity, and increased calpain-2 expression. Our findings suggest that NM IIA promotes 2-D epithelial cell migration but antagonizes 3-D invasion. These observations indicate multiple functions for NM IIA, which, along with the regulation of the F-actin cytoskeleton and cell-matrix adhesions, involve previously unrecognized control of intracellular signaling and protein expression.

  • 2.
    Babbin, Brian A.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Laukoetter, Mike G.
    Department of General Surgery, University of Muenster, Muenster, Germany.
    Nava, Porfirio
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Lee, Winston Y.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Peatman, Eric
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Severson, Eric A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Flower, Roderick J.
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Perretti, Mauro
    The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Annexin A1 regulates intestinal mucosal injury, inflammation, and repair2008In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, J Immunol, Vol. 181, no 7, p. 5035-5044Article in journal (Refereed)
    Abstract [en]

    During mucosal inflammation, a complex array of proinflammatory and protective mechanisms regulates inflammation and severity of injury. Secretion of anti-inflammatory mediators is a mechanism that is critical in controlling inflammatory responses and promoting epithelial restitution and barrier recovery. AnxA1 is a potent anti-inflammatory protein that has been implicated to play a critical immune regulatory role in models of inflammation. Although AnxA1 has been shown to be secreted in intestinal mucosal tissues during inflammation, its potential role in modulating the injury/inflammatory response is not understood. In this study, we demonstrate that AnxA1-deficient animals exhibit increased susceptibility to dextran sulfate sodium (DSS)-induced colitis with greater clinical morbidity and histopathologic mucosal injury. Furthermore, impaired recovery following withdrawal of DSS administration was observed in AnxA1 (-/-) animals compared with wild-type (WT) control mice that was independent of inflammatory cell infiltration. Since AnxA1 exerts its anti-inflammatory properties through stimulation of ALX/FPRL-1, we explored the role of this receptor-ligand interaction in regulating DSS-induced colitis. Interestingly, treatment with an ALX/FPRL-1 agonist, 15-epi-lipoxin A4 reversed the enhanced sensitivity of AnxA1 (-/-) mice to DSS colitis. In contrast, 15-epi-lipoxin A4 did not significantly improve the severity of disease in WT animals. Additionally, differential expression of ALX/FPLR-1 in control and DSS-treated WT and AnxA1-deficient animals suggested a potential role for AnxA1 in regulating ALX/FPRL-1 expression under pathophysiological conditions. Together, these results support a role of endogenous AnxA1 in the protective and reparative properties of the intestinal mucosal epithelium.

  • 3.
    Baumeister, Ulf
    et al.
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Funke, Ruth
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Ebnet, Klaus
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany.
    Vorschmitt, Henrik
    Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Koch, Stefan
    Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Vestweber, Dietmar
    Institute of Cell Biology, ZMBE, University of Münster, Münster, Germany; Max‐Planck‐Institute of Molecular Biomedicine, Münster, Germany.
    Association of Csk to VE-cadherin and inhibition of cell proliferation2005In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 24, no 9, p. 1686-1695Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial cadherin (VE-cadherin) mediates contact inhibition of cell growth in quiescent endothelial cell layers. Searching for proteins that could be involved in VE-cadherin signaling, we found the cytosolic C-terminal Src kinase (Csk), a negative regulator of Src family kinases. We show that Csk binds via its SH2 domain to the phosphorylated tyrosine 685 of VE-cadherin. VE-cadherin recruits Csk to cell contacts and both proteins can be co-precipitated from cell lysates of transfected cells and endothelial cells. Association of VE-cadherin and Csk in endothelial cells increased with increasing cell density. CHO cells expressing the tyrosine replacement mutant VE-cadherin-Y685F grow to higher cell densities than cells expressing wild-type VE-cadherin. Overexpression of Csk in these cells under an inducible promoter inhibits cell proliferation in the presence and absence of VE-cadherin, but not in the presence of VE-cadherin-Y685F. Reduction of Csk expression by RNA interference enhances endothelial cell proliferation. Our results suggest that the phosphorylated tyrosine residue 685 of VE-cadherin and probably the binding of Csk to this site are involved in inhibition of cell growth triggered by cell density.

  • 4.
    Berger, Birgit S.
    et al.
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Acebron, Sergio P.
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Herbst, Jessica
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Koch, Stefan
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany.
    Niehrs, Christof
    Division of Molecular Embryology, DKFZ‐ZMBH Alliance, Heidelberg, Germany; Institute of Molecular Biology, Mainz, Germany.
    Parkinson's disease-associated receptor GPR37 is an ER chaperone for LRP62017In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 18, no 5, p. 712-725Article in journal (Refereed)
    Abstract [en]

    Wnt/beta-catenin signaling plays a key role in embryonic development, stem cell biology, and neurogenesis. However, the mechanisms of Wnt signal transmission, notably how the receptors are regulated, remain incompletely understood. Here we describe that the Parkinson's disease-associated receptor GPR37 functions in the maturation of the N-terminal bulky beta-propellers of the Wnt co-receptor LRP6. GPR37 is required for Wnt/beta-catenin signaling and protects LRP6 from ER-associated degradation via CHIP (carboxyl terminus of Hsc70-interacting protein) and the ATPase VCP GPR37 is highly expressed in neural progenitor cells (NPCs) where it is required for Wnt-dependent neurogenesis. We conclude that GPR37 is crucial for cellular protein quality control during Wnt signaling.

  • 5.
    Capaldo, Christopher T.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Kwon, Michael
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Laur, Oskar
    Yerkes-Microbiology, Emory University, Atlanta, GA, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Atlanta, GA, USA.
    Tight function zonula occludens-3 regulates cyclin D1-dependent cell proliferation2011In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 22, no 10, p. 1677-1685Article in journal (Refereed)
    Abstract [en]

    Coordinated regulation of cell proliferation is vital for epithelial tissue homeostasis, and uncontrolled proliferation is a hallmark of carcinogenesis. A growing body of evidence indicates that epithelial tight junctions (TJs) play a role in these processes, although the mechanisms involved are poorly understood. In this study, we identify and characterize a novel plasma membrane pool of cyclin D1 with cell-cycle regulatory functions. We have determined that the zonula occludens (ZO) family of TJ plaque proteins sequesters cyclin D1 at TJs during mitosis, through an evolutionarily conserved class II PSD-95, Dlg, and ZO-1 (PDZ)-binding motif within cyclin D1. Disruption of the cyclin D1/ZO complex through mutagenesis or siRNA-mediated suppression of ZO-3 resulted in increased cyclin D1 proteolysis and G(0)/G(1) cell-cycle retention. This study highlights an important new role for ZO family TJ proteins in regulating epithelial cell proliferation through stabilization of cyclin D1 during mitosis.

  • 6.
    Heidemann, Jan
    et al.
    Department of Medicine B University of Münster, Münster, Germany.
    Ruther, Christoph
    Department of Medicine B University of Münster, Münster, Germany.
    Kebschull, Moritz
    Department of Medicine B University of Münster, Münster, Germany.
    Domschke, Wolfram
    Department of Medicine B University of Münster, Münster, Germany.
    Bruwer, Matthias
    Department of General Surgery University of Münster, Münster, Germany.
    Koch, Stefan
    Department of Medicine B University of Münster, Münster, Germany.
    Kucharzik, Torsten
    Department of Medicine B University of Münster, Münster, Germany.
    Maaser, Christian
    Department of Medicine B University of Münster, Münster, Germany.
    Expression of IL-12-related molecules in human intestinal microvascular endothelial cells is regulated by TLR32007In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Am J Physiol Gastrointest Liver Physiol, Vol. 293, no 6, p. G1315-G1324Article in journal (Refereed)
    Abstract [en]

    Members of the interleukin (IL)-12 family constitute subunits of IL-12, -23, and -27. These ILs represent pivotal mediators in the regulation of cell-mediated immune responses and in animal models of human inflammatory bowel disease. Recent work has suggested that intestinal endothelial cells might serve as a second line of defense in bacterial sensing of invading pathogens. The purpose of this study was to examine the production of IL-12 family members in intestinal endothelial cells (HIMEC). HIMEC were stimulated with proinflammatory agents (TNF-alpha, IFN-gamma, IL-1beta) and microbial antigens [LPS, lipoteichoic acid, peptidoglycan, CpG-DNA, flagellin, poly(I:C)]. Expression of IL-12 family members and of Toll-like receptor (TLR)3 in HIMEC was assessed by real-time RT-PCR, immunostaining, flow cytometry, and immunoblot analysis. HIMEC display an induction of Epstein-Barr virus-induced gene 3 (EBI3), IL-12p35, and IL-23p19, whereas no expression of IL-12p40 and IL-27p28 was detectable. The strongest induction was induced by proinflammatory factors known to utilize the NF-kappaB pathway, and expression of EBI3 and IL-23p19 was diminished by an NF-kappaB inhibitor. HIMEC display regulated expression of TLR3. Adhesion and transmigration assays showed proinflammatory responses after HIMEC stimulation. HIMEC are capable of producing IL-12 family members as a response to microbial stimuli. The TLR3 agonist, poly(I:C), was shown to enhance leukocyte adhesion in vitro in HIMEC. Our data suggest that the intestinal microvasculature is responsive to ligands of TLR3 expressed on intestinal endothelial cells, thereby adding to the regulation of adaptive immunity and leukocyte recruitment.

  • 7.
    Khounlotham, Manirath
    et al.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Kim, Wooki
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Peatman, Eric
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nava, Porfirio
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Medina-Contreras, Oscar
    Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
    Addis, Caroline
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Fournier, Benedicte
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Denning, Timothy L.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
    Parkos, Charles A.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Compromised intestinal epithelial barrier induces adaptive immune compensation that protects from colitis2012In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 37, no 3, p. 563-573Article in journal (Refereed)
    Abstract [en]

    Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-beta-producing CD4(+) T cells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) T cells and TGF-beta. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.

  • 8.
    Kirsch, Nadine
    et al.
    Deutsch Krebsforschungszentrum DKFZ, Germany.
    Chang, Ling-Shih
    Deutsch Krebsforschungszentrum DKFZ, Germany.
    Koch, Stefan
    Deutsch Krebsforschungszentrum DKFZ, Germany.
    Glinka, Andrey
    Deutsch Krebsforschungszentrum DKFZ, Germany.
    Dolde, Christine
    Deutsch Krebsforschungszentrum DKFZ, Germany.
    Colozza, Gabriele
    University of Calif Los Angeles, CA 90095 USA; University of Calif Los Angeles, CA 90095 USA.
    Benitez, Maria D. J.
    University of Calif Los Angeles, CA 90095 USA; University of Calif Los Angeles, CA 90095 USA.
    De Robertis, Edward M.
    University of Calif Los Angeles, CA 90095 USA; University of Calif Los Angeles, CA 90095 USA.
    Niehrs, Christof
    Deutsch Krebsforschungszentrum DKFZ, Germany; Institute Molecular Biol, Germany.
    Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover2017In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 43, no 1, p. 71-+Article in journal (Refereed)
    Abstract [en]

    Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation ofWnt/b-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function ofANGPTL4 invites reinterpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

  • 9.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Extrinsic control of Wnt signaling in the intestine2017In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 97, p. 1-8Article, review/survey (Refereed)
    Abstract [en]

    The canonical Wnt/beta-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers.

  • 10.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Parkos, Charles A.
    Department of Pathology and Laboratory Medicine, Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, USA.
    The Epithelial Barrier2013In: Molecular Genetics of Inflammatory Bowel Disease / [ed] D'Amato M., Rioux J., Springer Science+Business Media B.V., 2013, p. 265-280Chapter in book (Refereed)
  • 11.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Who controls the Wnt?2019In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 108Article in journal (Other academic)
    Abstract [en]

    n/a

  • 12.
    Koch, Stefan
    et al.
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany.
    Acebron, Sergio P.
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany.
    Herbst, Jessica
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany.
    Hatiboglu, Gencay
    Department of Urology, University of Heidelberg, Heidelberg, Germany.
    Niehrs, Christof
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, Heidelberg, Germany; Institute of Molecular Biology (IMB), Mainz, Germany.
    Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 163, no 5, p. 1225-1236Article in journal (Refereed)
    Abstract [en]

    The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically relevant roles beyond beta-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post-transcriptional sperm maturation program and invite revisiting transcription-independent Wnt signaling in somatic cells as well.

  • 13.
    Koch, Stefan
    et al.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Capaldo, C. T.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Hilgarth, R. S.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Fournier, B.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Parkos, C. A.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Nusrat, A.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
    Protein kinase CK2 is a critical regulator of epithelial homeostasis in chronic intestinal inflammation2013In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 6, no 1, p. 136-145Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms that restore intestinal epithelial homeostasis during colitis are incompletely understood. Here, we report that during intestinal inflammation, multiple inflammatory cytokines promote the activity of a master regulator of cell proliferation and apoptosis, serine/threonine kinase CK2. Enhanced mucosal CK2 protein expression and activity were observed in animal models of chronic colitis, particularly within intestinal epithelial cells (IECs). The in vitro treatment of intestinal epithelial cell lines with cytokines resulted in increased CK2 expression and nuclear translocation of its catalytic alpha subunit. Similarly, nuclear translocation of CK2alpha was a prominent feature observed in colonic crypts from individuals with ulcerative colitis and Crohn's disease. Further in vitro studies revealed that CK2 activity promotes epithelial restitution, and protects normal IECs from cytokine-induced apoptosis. These observations identify CK2 as a key regulator of homeostatic properties of the intestinal epithelium that serves to promote wound healing, in part through inhibition of apoptosis under conditions of inflammation.

  • 14.
    Koch, Stefan
    et al.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Samarin, Stanislav
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nava, Porfirio
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Neumaier, Irmgard
    Biologische Chemie, Technische Universitaet Muenchen, D-85350 Freising-Weihenstephan, Germany.
    Skerra, Arne
    Biologische Chemie, Technische Universitaet Muenchen, D-85350 Freising-Weihenstephan, Germany.
    Sacks, David B.
    Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells2009In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 20, no 22, p. 4816-4825Article in journal (Refereed)
    Abstract [en]

    Wnt signaling pathways regulate proliferation, motility, and survival in a variety of human cell types. Dickkopf-1 (Dkk-1) is a secreted Wnt antagonist that has been proposed to regulate tissue homeostasis in the intestine. In this report, we show that Dkk-1 is secreted by intestinal epithelial cells after wounding and that it inhibits cell migration by attenuating the directional orientation of migrating epithelial cells. Dkk-1 exposure induced mislocalized activation of Cdc42 in migrating cells, which coincided with a displacement of the polarity protein Par6 from the leading edge. Consequently, the relocation of the microtubule organizing center and the Golgi apparatus in the direction of migration was significantly and persistently inhibited in the presence of Dkk-1. Small interfering RNA-induced down-regulation of Dkk-1 confirmed that extracellular exposure to Dkk-1 was required for this effect. Together, these data demonstrate a novel role of Dkk-1 in the regulation of directional polarization of migrating intestinal epithelial cells, which contributes to the effect of Dkk-1 on wound closure in vivo.

  • 15.
    Koch, Stefan
    et al.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Kucharzik, T.
    Department of Gastroenterology, Municipal Hospital of Lueneburg, Lueneburg.
    Heidemann, J.
    Department of Medicine B, University Hospital of Muenster, Muenster, Germany.
    Nusrat, A.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Luegering, A.
    Department of Medicine B, University Hospital of Muenster, Muenster, Germany.
    Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 161, no 2, p. 332-341Article in journal (Refereed)
    Abstract [en]

    Infiltrating monocytes and macrophages contribute to the initiation and perpetuation of mucosal inflammation characteristic for human inflammatory bowel disease (IBD). Peripheral blood monocytes expressing the low-affinity Fcgamma receptor CD16 have been identified previously as a major proinflammatory cell population, based on their unique cytokine secretion profile. However, the contribution of these cells to the pathogenesis of inflammatory bowel disease remains to be elucidated. Thus, in this study we investigated whether the peripheral CD16(+) monocyte count correlates with common IBD disease parameters, and whether these cells infiltrate the intestinal mucosa under inflammatory conditions. We observed that CD16(+) peripheral blood monocytes are increased significantly in active Crohn's disease, particularly in patients with high Crohn's disease activity index and colonic involvement. Furthermore, we found that CD16(+) cells are a major contributor to the inflammatory infiltrate in Crohn's disease mucosa, although their spontaneous migration through primary human intestinal endothelial cells is limited. Our data suggest that lamina propria, but not peripheral blood, CD16(+) monocytes are a crucial proinflammatory cell population in IBD, and a potential target for anti-inflammatory therapy.

  • 16.
    Koch, Stefan
    et al.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Nava, Porfirio
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Addis, Caroline
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Kim, Wooki
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pediatrics, Emory University, Atlanta, Georgia.
    Denning, Timothy L.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; Department of Pediatrics, Emory University, Atlanta, Georgia.
    Li, Linheng
    Stowers Institute for Medical Research, Kansas City, Missouri.
    Parkos, Charles A.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    Nusrat, Asma
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
    The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair2011In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 141, no 1, p. 259-268Article in journal (Refereed)
    Abstract [en]

    Background & Aims

    Dkk1 is a secreted antagonist of the Wnt/β-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine.

    Methods

    We used doubleridge mice (Dkk1d/d), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/β-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2′-deoxyuridine incorporation, and immunostaining.

    Results

    Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of β-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/dmice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/β-catenin, ERK/Elk-1, and c-Jun pathways.

    Conclusions

    Dkk1, an antagonist of Wnt/β-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.

  • 17.
    Koch, Stefan
    et al.
    Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
    Nusrat, Asma
    Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
    Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions2009In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1165, p. 220-227Article in journal (Refereed)
    Abstract [en]

    In the intestine, a single layer of epithelial cells effectively separates potentially harmful luminal content from the underlying tissue. The importance of an intact mucosal layer is highlighted by pathological disorders of the gut such as inflammatory bowel disease, in which disruption of the epithelial barrier leads to severe inflammation of the submucosal tissue compartments. Epithelial barrier function is provided by tightly regulated intercellular junctions, which consist of a plethora of membrane-associated and transmembrane proteins organized in discreet, spatially restricted complexes. Classically, these complexes are known to be dynamic seals for fluids and small molecules, as well as to provide mechanical strength by anchoring cell-cell contacts to the cytoskeleton. Rather than just acting as simple gates and adapters, however, junctional complexes themselves can relay extracellular stimuli to the epithelium and initiate cellular responses such as differentiation and apoptosis. In this review, we will highlight recent studies by our group and others which discuss how junctional proteins can promote outside-to-inside signaling and modulate epithelial cell fate. Unraveling the complex crosstalk between epithelial cells and their intercellular junctions is essential to understanding how epithelial barrier function is maintained in vivo and might provide new strategies for the treatment of inflammatory disorders of the intestine.

  • 18.
    Koch, Stefan
    et al.
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
    Nusrat, Asma
    Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
    The life and death of epithelia during inflammation: lessons learned from the gut2012In: Annual Review of Pathology, ISSN 1553-4006, E-ISSN 1553-4014, Vol. 7, p. 35-60Article in journal (Refereed)
    Abstract [en]

    Epithelial cells form protective barriers that physically separate an organism from the outside world. Rather than being merely static, impregnable shields, epithelia are highly dynamic structures that can adjust their proliferation, differentiation, and death in response to intrinsic and extrinsic signals. The advantages as well as pitfalls of this flexibility are highlighted in inflammatory disorders such as inflammatory bowel diseases and psoriasis, which are characterized by a chronically dysregulated homeostasis of the epithelium. In recent years, it has become increasingly apparent that epithelial cells communicate with their surroundings through converging, integrated signaling cascades and that even minor alterations in these pathways can have dramatic pathologic consequences. In this review, we discuss how inflammatory cytokines and other signaling molecules, directly or through cross talk, regulate epithelial homeostasis in the intestine, and we highlight parallels and differences in a few other organs.

  • 19.
    Lugering, Andreas
    et al.
    Department of Medicine B, University of Münster, Münster, Germany.
    Lebiedz, Pia
    Department of Medicine B, University of Münster, Münster, Germany.
    Koch, Stefan
    Department of Medicine B, University of Münster, Münster, Germany.
    Kucharzik, Torsten
    Department of Medicine B, University of Münster, Münster, Germany.
    Apoptosis as a therapeutic tool in IBD?2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1072, p. 62-77Article in journal (Refereed)
    Abstract [en]

    Defective apoptosis of mucosal cell populations seems to be a relevant pathogenetic mechanism in inflammatory bowel disease (IBD). It has been suggested that the induction of apoptosis in various effector cells may be a relevant therapeutic mechanism in IBD. Indeed, it was shown that different drugs used for treatment of IBD have the capacity to induce apoptosis in T cells or monocytes in vitro and in vivo. However, it remains unclear whether these observations are related to clinical efficacy of these agents. TNF-alpha is one of the most relevant proinflammatory mediators in IBD and anti-TNF treatment has been shown to be of particular benefit for patients with IBD. It could subsequently be shown that various anti-TNF-alpha agents, such as infliximab and adalimumab, can induce apoptosis in activated monocytes and lymphocytes in vitro and in vivo. This mechanism requires reverse signaling via transmembranous TNF, thereby eliciting a signal transduction cascade that results in programmed cell death. Although other mechanisms might also contribute to the clinical effect of anti-TNF-alpha, current data suggest that apoptosis is a relevant mechanism that is associated with clinical efficacy of anti-TNF agents. Induction of apoptosis in activated monocytes or T cells may be regarded as therapeutic tool not only for anti-TNF agents, but also for other drugs used in IBD. Future strategies should focus on identification of mechanisms that prevent apoptosis in the mucosa of patients with IBD and in targeting apoptotic pathways as a therapeutic strategy in IBD.

  • 20.
    Martins, Leila R.
    et al.
    Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany.
    Bung, Raffaela K.
    Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany.
    Koch, Stefan
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
    Richter, Karsten
    Core Facility Electron Microscopy, DKFZ, 69120 Heidelberg, Germany.
    Schwarzmüller, Laura
    Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany.
    Terhardt, Dorothee
    Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany.
    Kurtulmus, Bahtiyar
    Molecular Biology of Centrosomes and Cilia Unit, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
    Niehrs, Christof
    Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany; Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
    Rouhi, Arefeh
    Department of Internal Medicine III, Ulm University, 89081 Ulm, Germany.
    Lohmann, Ingrid
    Department of Developmental Biology, Centre for Organismal Studies (COS), 69120 Heidelberg, Germany.
    Pereira, Gislene
    Molecular Biology of Centrosomes and Cilia Unit, DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
    Fröhling, Stefan
    Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
    Glimm, Hanno
    Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
    Scholl, Claudia
    Division of Applied Functional Genomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
    Stk33 is required for spermatid differentiation and male fertility in mice2018In: Developmental Biology, ISSN 0012-1606, E-ISSN 1095-564X, Vol. 433, no 1, p. 84-93Article in journal (Refereed)
    Abstract [en]

    Spermiogenesis is the final phase during sperm cell development in which round spermatids undergo dramatic morphological changes to generate spermatozoa. Here we report that the serine/threonine kinase Stk33 is essential for the differentiation of round spermatids into functional sperm cells and male fertility. Constitutive Stk33 deletion in mice results in severely malformed and immotile spermatozoa that are particularly characterized by disordered structural tail elements. Stk33 expression first appears in primary spermatocytes, and targeted deletion of Stk33 in these cells recapitulates the defects observed in constitutive knockout mice, confirming a germ cell-intrinsic function. Stk33 protein resides in the cytoplasm and partially co-localizes with the caudal end of the manchette, a transient structure that guides tail elongation, in elongating spermatids, and loss of Stk33 leads to the appearance of a tight, straight and elongated manchette. Together, these results identify Stk33 as an essential regulator of spermatid differentiation and male fertility.

  • 21.
    Nava, Porfirio
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Koch, Stefan
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Kolegraff, Keli
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Rankin, Carl Robert
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Farkas, Attila E.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA; Institute of Biophysics, Biological Research Center, Szeged, Hungary.
    Feasel, Mattie E.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Li, Linheng
    Stowers Institute for Medical Research, Kansas City, Missouri, USA.
    Addis, Caroline
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology, Emory University, Whitehead Biomedical Research Building, Atlanta, Georgia, USA.
    JAM-A regulates epithelial proliferation through Akt/beta-catenin signalling2011In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 12, no 4, p. 314-20Article in journal (Refereed)
    Abstract [en]

    Expression of the tight junction protein junctional adhesion molecule-A (JAM-A) has been linked to proliferation and tumour progression. However, a direct role for JAM-A in regulating proliferative processes has not been shown. By using complementary in vivo and in vitro approaches, we demonstrate that JAM-A restricts intestinal epithelial cell (IEC) proliferation in a dimerization-dependent manner, by inhibiting Akt-dependent beta-catenin activation. Furthermore, IECs from transgenic JAM-A(-/-)/beta-catenin/T-cell factor reporter mice showed enhanced beta-catenin-dependent transcription. Finally, inhibition of Akt reversed colonic crypt hyperproliferation in JAM-A-deficient mice. These data establish a new link between JAM-A and IEC homeostasis.

  • 22.
    Nava, Porfirio
    et al.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Mexico City, Mexico.
    Kamekura, Ryuta
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Quiros, Miguel
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Medina-Contreras, Oscar
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
    Hamilton, Ross W.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Kolegraff, Keli N.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Koch, Stefan
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Division of Molecular Embryology, German Cancer Research Center, Heidelberg, Germany.
    Candelario, Aurora
    Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Mexico City, Mexico.
    Romo-Parra, Hector
    Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, Mexico City, Mexico; Institute of Physiology I (Neurophysiology), Westfälische Wilhelms-University Münster, Münster, Germany.
    Laur, Oskar
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Hilgarth, Roland S.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Denning, Timothy L.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
    Parkos, Charles A.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    IFN gamma-induced suppression of beta-catenin signaling: evidence for roles of Akt and 14.3.3 zeta2014In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 25, no 19, p. 2894-2904Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine interferon gamma (IFNgamma ) influences intestinal epithelial cell (IEC) homeostasis in a biphasic manner by acutely stimulating proliferation that is followed by sustained inhibition of proliferation despite continued mucosal injury. beta-Catenin activation has been classically associated with increased IEC proliferation. However, we observed that IFNgamma inhibits IEC proliferation despite sustained activation of Akt/beta-catenin signaling. Here we show that inhibition of Akt/beta-catenin-mediated cell proliferation by IFNgamma is associated with the formation of a protein complex containing phosphorylated beta-catenin 552 (pbeta-cat552) and 14.3.3zeta. Akt1 served as a bimodal switch that promotes or inhibits beta-catenin transactivation in response to IFNgamma stimulation. IFNgamma initially promotes beta-catenin transactivation through Akt-dependent C-terminal phosphorylation of beta-catenin to promote its association with 14.3.3zeta. Augmented beta-catenin transactivation leads to increased Akt1 protein levels, and active Akt1 accumulates in the nucleus, where it phosphorylates 14.3.3zeta to translocate 14.3.3zeta/beta-catenin from the nucleus, thereby inhibiting beta-catenin transactivation and IEC proliferation. These results outline a dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.

  • 23.
    Nava, Porfirio
    et al.
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Laukoetter, Mike G.
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of General Surgery, Universitaet Muenster, Muenster, Germany.
    Lee, Winston Y.
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Kolegraff, Keli
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Capaldo, Christopher T.
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Beeman, Neal
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Addis, Caroline
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Gerner-Smidt, Kirsten
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Neumaier, Irmgard
    Biologische Chemie, Technische Universitaet Muenchen, Freising-Weihenstephan, Germany.
    Skerra, Arne
    Biologische Chemie, Technische Universitaet Muenchen, Freising-Weihenstephan, Germany.
    Li, Linheng
    Stowers Institute for Medical Research, Kansas City, MO, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
    Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways2010In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 32, no 3, p. 392-402Article in journal (Refereed)
    Abstract [en]

    Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways.

  • 24.
    Neumann, Philipp-Alexander
    et al.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia; Department of General and Visceral Surgery, University of Muenster, Muenster, Germany.
    Koch, Stefan
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia; Division of Molecular Embryology, German Cancer Research Center, Heidelberg, Germany.
    Hilgarth, Roland S.
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia.
    Perez-Chanona, Ernesto
    Department of Pharmacology, University of North Carolina,Chapel Hill, Chapel Hill, North Carolina.
    Denning, Patricia
    Department of Pediatrics, Emory University, Atlanta, Georgia.
    Jobin, Christian
    Department of Infectious Diseases and Pathology, University of Florida, Gainesville, Florida.
    Nusrat, Asma
    Epithelial Pathobiology and Mucosal Inflammation Research Unit, Emory University, Atlanta, Georgia.
    Gut commensal bacteria and regional Wnt gene expression in the proximal versus distal colon2014In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Am J Pathol, Vol. 184, no 3, p. 592-9Article in journal (Refereed)
    Abstract [en]

    Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/beta-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria.

  • 25.
    Samarin, Stanislav N.
    et al.
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Ivanov, Andrei I.
    Department of Medicine, University of Rochester, Rochester, NY, USA.
    Parkos, Charles A.
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Nusrat, Asma
    Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
    Coronin 1C negatively regulates cell-matrix adhesion and motility of intestinal epithelial cells2010In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 391, no 1, p. 394-400Article in journal (Refereed)
    Abstract [en]

    Coronins, WD-repeat actin-binding proteins, are known to regulate cell motility by coordinating actin filament turnover in lamellipodia of migrating cell. Here we report a novel mechanism of Coronin 1C-mediated cell motility that involves regulation of cell-matrix adhesion. RNAi silencing of Coronin 1C in intestinal epithelial cells enhanced cell migration and modulated lamellipodia dynamics by increasing the persistence of lamellipodial protrusion. Coronin 1C-depleted cells showed increased cell-matrix adhesions and enhanced cell spreading compared to control cells, while over-expression of Coronin 1C antagonized cell adhesion and spreading. Enhanced cell-matrix adhesion of coronin-deficient cells correlated with hyperphosphorylation of focal adhesion kinase (FAK) and paxillin, and an increase in number of focal adhesions and their redistribution at the cell periphery. siRNA depletion of FAK in coronin-deficient cells rescued the effects of Coronin 1C depletion on motility, cell-matrix adhesion, and spreading. Thus, our findings provide the first evidence that Coronin 1C negatively regulates epithelial cell migration via FAK-mediated inhibition of cell-matrix adhesion.

1 - 25 of 25
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