<i>Bacteroides fragilis</i> toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage

Wu, Shaoguang; Rhee, Ki Jong; Zhang, Ming; Franco, Augusto A.; Sears, Cynthia L.

doi:10.1242/jcs.03455

Cited by 216 publications

(119 citation statements)

References 52 publications

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“…We also observe a similar cleavage product in response to staurosporine in MCF-7 and MDCK epithelial cells. Recently, Bacteroides fragilis toxin was also reported to stimulate ␥-secretase-induced cleavage of E-cadherin (52). However, the physiological stimuli that induce the production of E-cad/CTF2 were not clear.…”

Section: Discussionmentioning

confidence: 99%

A Role for the Cleaved Cytoplasmic Domain of E-cadherin in the Nucleus

Ferber

Kajita

Wadlow

et al. 2008

Journal of Biological Chemistry

141

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Cell-cell contacts play a vital role in intracellular signaling, although the molecular mechanisms of these signaling pathways are not fully understood. E-cadherin, an important mediator of cell-cell adhesions, has been shown to be cleaved by ␥-secretase. This cleavage releases a fragment of E-cadherin, E-cadherin C-terminal fragment 2 (E-cad/CTF2), into the cytosol. Here, we study the fate and function of this fragment. First, we show that coexpression of the cadherin-binding protein, p120 catenin (p120), enhances the nuclear translocation of E-cad/CTF2. By knocking down p120 with short interfering RNA, we also demonstrate that p120 is necessary for the nuclear localization of E-cad/CTF2. Furthermore, p120 enhances and is required for the specific binding of E-cad/CTF2 to DNA. Finally, we show that E-cad/CTF2 can regulate the p120-Kaiso-mediated signaling pathway in the nucleus. These data indicate a novel role for cleaved E-cadherin in the nucleus.In multicellular organisms, individual cells are often connected with each other via cell-cell adhesions to form threedimensionally structured tissues or organs. Formation of tight and compact cell-cell adhesions suppresses free cell movement and provides cells with a positional cue for the establishment of cell polarity. In addition to the structural roles, it has been long known that cell-cell contacts play an important role in various signal transduction pathways (1, 2). In other words, through cell-cell contacts, cells can exchange a variety of information with their neighbors to behave properly in their community.Cadherins are a family of transmembrane cell-cell adhesion proteins that can be subdivided into several groups including classical cadherins and protocadherins (3). Classical cadherins, of which E-cadherin is the best characterized, play a crucial role in mediating cell-cell contacts at adherens junctions. The extracellular domains of classical cadherins form homophilic ligations. The cytoplasmic domain of cadherin includes two cadherin homology (CH) 2 domains: CH2 domain (located at the membrane proximal region) and CH3 domain (located at the distal region). These domains are conserved between classical cadherins. The CH2 and CH3 domains of cadherins interact with p120-catenin (p120) and ␤-catenin, respectively (4, 5). Furthermore, the CH2 domain of E-cadherin also interacts with Hakai (6, 7).Cadherins, especially classical cadherins, have been shown to be involved in several signaling pathways regulating cell proliferation, differentiation, and survival (8 -11). However, the molecular mechanisms whereby cadherins regulate varied cellular processes are not fully understood. The cytoplasmic domain of cadherins does not possess any intrinsic enzymatic activity that could directly mediate signaling pathways in the cytosol. However, cadherin-binding proteins, especially ␤-catenin and p120, have been shown to localize in the nucleus and play a key role in signal transduction. The crucial role of ␤-catenin in the canonical Wnt signaling pathway has been well...

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Section: Discussionmentioning

confidence: 99%

A Role for the Cleaved Cytoplasmic Domain of E-cadherin in the Nucleus

Ferber

Kajita

Wadlow

et al. 2008

Journal of Biological Chemistry

141

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“…This is of particular interest as enteric pathogens, such as E. coli and Campylobacter, can increase mucosal permeability during the acute phase of the infection [41][42][43]. In addition, recent genetic studies have identified a link between variants in the same region of the gene, as found in this study, with susceptibility to colorectal cancer [44], ulcerative colitis [45] and Crohn's disease [46].…”

Section: Discussionmentioning

confidence: 69%

Bacteria, genetics and irritable bowel syndrome

Craig¹,

Quigley²

2010

Expert Review of Gastroenterology & Hepatology

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EVALUATION OF: Villani AC, Lemire M, Thabane M et al. Genetic risk factors for post-infectious irritable bowel syndrome following a waterborne outbreak of gastroenteritis. Gastroenterology 138, 1502-1513 (2010). While the pathogenesis of irritable bowel syndrome (IBS) remains to be fully defined, two clinical observations - the occurrence, de novo, of IBS following bacterial gastroenteritis and the history, commonly obtained from IBS patients, of other instances of the syndrome within their families - have instigated investigations, in IBS, of the potential roles, on the one hand, of the gut microbiota and the host response and, on the other hand, of genetic factors. The study reviewed here relates to both of these factors by studying genetic predisposition to postinfective IBS in a large population of individuals who were exposed to a multimicrobial enteric infection, which resulted in a severe outbreak of gastroenteritis and was followed by the development of IBS in over a third. In this detailed study, the investigators identified a number of genes that were linked significantly to the development of postinfectious-IBS in the Toll-like receptor 9, IL-6 and cadherin 1 regions. These genes play important roles in bacterial recognition, the inflammatory response and epithelial integrity, respectively, and provide considerable support for the hypothesis that links IBS onset to disturbances in the microbiota and the host response.

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“…Internalin A from Listeria monocytogenes [43,44] and invasion Als3 from Candida albicans interact with E-cadherin to allow the internalization of the respective microorganisms. The metalloproteinase toxin BFT from Bacteroides fragilis was shown to induce the shedding of the E-cadherin ectodomain through an unknown IEC receptor-mediated induction of g-secretase [45]. Also trypsin-like serine protease HpHtrA from Helicobacter pylori can produce E-cadherin cleavage.…”

Section: Gut Microbiota Sustains Intestinal Damagementioning

confidence: 99%

Gut Microbiota: A Key Modulator of Intestinal Healing in Inflammatory Bowel Disease

Lopetuso

Petito

Zambrano

et al. 2016

Dig Dis

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Mucosal healing (MH) represents a crucial factor for maintaining gut homeostasis. Indeed, in inflammatory bowel disease, MH has become the standard therapeutical target, because it is associated with more effective disease control, more frequent steroid-free remission, lower rates of hospitalization and surgery, and improved quality of life. In this scenario, gut microbiota is a crucial player in modulating intestinal repair and regeneration process. It can act on the tumor necrosis factor-α production, modulation of reactive oxygen and nitrogen species, activity of matrix metalloproteinases and on many other mechanisms strictly involved in restoring gut health. In this review, we analyze and review the literature on the role of gut microbiota in sustaining mucosal injury and achieving MH.

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Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and γ-secretase-dependent E-cadherin cleavage

Cited by 216 publications

References 52 publications

A Role for the Cleaved Cytoplasmic Domain of E-cadherin in the Nucleus

A Role for the Cleaved Cytoplasmic Domain of E-cadherin in the Nucleus

Bacteria, genetics and irritable bowel syndrome

Gut Microbiota: A Key Modulator of Intestinal Healing in Inflammatory Bowel Disease

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