Abstract
Once bound to the epithelium, pathogenic bacteria have to cross epithelial barriers to invade their human host. In order to achieve this goal, they have to destroy the adherens junctions insured by cell adhesion molecules (CAM), such as E-cadherin (E-cad). The invasive bacteria use more or less sophisticated mechanisms aimed to deregulate CAM genes expression or to modulate the cell-surface expression of CAM proteins, which are otherwise rigorously regulated by a molecular crosstalk essential for homeostasis. Apart from the repression of CAM genes, a drastic decrease in adhesion molecules on human epithelial cells can be obtained by induction of eukaryotic endoproteases named sheddases or through synthesis of their own (prokaryotic) sheddases. Cleavage of CAM by sheddases results in the release of soluble forms of CAM. The overexpression of soluble CAM in body fluids can trigger inflammation and pro-carcinogenic programming leading to tumor induction and metastasis. In addition, the reduction of the surface expression of E-cad on epithelia could be accompanied by an alteration of the anti-bacterial and anti-tumoral immune responses. This immune response dysfunction is likely to occur through the deregulation of immune cells homing, which is controlled at the level of E-cad interaction by surface molecules αE integrin (CD103) and lectin receptor KLRG1. In this review, we highlight the central role of CAM cell-surface expression during pathogenic microbial invasion, with a particular focus on bacterial-induced cleavage of E-cad. We revisit herein the rapidly growing body of evidence indicating that high levels of soluble E-cad (sE-cad) in patients’ sera could serve as biomarker of bacterial-induced diseases.
Epithelial Cadherin in Cell-to-Cell Adhesion and Cell Activation
Cadherins (cad) belong to the superfamily of cell-adhesion molecules (CAMs) (Takeichi, 1977; Nollet et al., 2000; Angst et al., 2001; Hulpiau and van Roy, 2009). Characterized by their adhesion properties mediated through repeated extracellular cad domains (ECs) under Ca2+ control, cad play a key role in cell-to-cell interactions (Hyafil et al., 1981). Several subtypes of cad are encoded in the human genome (Oda and Takeichi, 2011). These molecules were classified according to their tissue distribution: for example, the P prefix is used in P-cad (encoded by CDH3) to define placental cad, N-cad (encoded by CDH2 and CDH12) for neural cad, VE-cad (encoded by CDH5) for vascular endothelial cad, and E-cadherin (E-cad) (encoded by CDH1) for epithelial cad. The CDH1 gene, located on chromosome 16q22.1, comprises 16 exons and 15 introns (Berx et al., 1995), and it is transcribed into a 4.5Kb pre-mRNA that is spliced to generate the E-cad mRNA. Transcriptional repression of CDH1 gene is achieved by a range of transcriptional repressors that bind its promoter, including members of the SNAIL and ZEB gene families of zinc-finger transcription factors (Cano et al., 2000; Bolós et al., 2003; Cadigan and Waterman, 2012). Repression of CDH1 gene can also be the result of CpG-island hypermethylation of its promoter, loss of heterozygosis at 16q22.1, and inactivating mutations (Berx et al., 1998; Lombaerts et al., 2006).
Initially described as liver cell adhesion molecule (L-CAM) and uvomorulin (Gallin et al., 1983; Schuh et al., 1986), E-cad is a single-pass type I transmembrane glycoprotein of 120 kDa that plays a major role in cell polarity, intercellular adhesion, and tissue integrity (Ogou et al., 1983; Niessen et al., 2011; van Roy, 2014). It possesses five EC repeats with binding sites for Ca2+ (Shapiro et al., 1995). These predominantly homophilic E-cad dimerize in cis at the cell’s surface and the homodimer can then interact in trans with an adjacent E-cad homodimer on a neighboring epithelial cell to form adherens junctions (Boggon, 2002). However, E-cad can also exhibit heterophilic interactions in trans with the αEβ7 integrin, also called CD103 antigen of T-lymphocytes, which generally lacks E-cad cell surface expression (Cepek et al., 1994; Sheridan and Lefrançois, 2011) as well as it can bind the killer cell lectin receptor G1 (KLRG1) expressed on T-lymphocytes and natural killer (NK) cells (Kilshaw, 1999; Ito et al., 2006). Over-expression of E-cad can delay the rate of cell migration (Hermiston et al., 1996). Loss of E-cad can reduce CD103+ T-cell antitumor activity (Shields et al., 2019). Under physiological conditions, E-cad interacts with p120-ctn and β-catenin (β-cat) via its intracytoplasmic tail (Nagafuchi and Takeichi, 1988; McCrea and Gumbiner, 1991; Kourtidis et al., 2013). The cytoplasmic tail of E-cad consists of the juxta membrane domain (JMD), which allows the clustering of cad and contributes to the adhesive strength via p120-ctn, and the cat-binding domain (CBD), which interacts with β-cat and γ-cat (Kemler, 1993; Yap et al., 1998). The α-cat links the bound β-cat and the actin cytoskeleton. Signaling through E-cad cytoplasmic tail is a complex process which involves multiple contacts with intracytoplasmic partners, whose diversity is just beginning to be elucidated by the characterization of the E-cad interactome (Guo et al., 2014). E-cad is a tumor suppressor acting through intracytoplasmic retention of β-catenin stocks and suppresses inflammatory signaling pathways (Figure 1).
Figure 1
E-Cadherin and Other Cadherin/Cell Adhesion Molecules Used as Target Receptors for Bacteria
Fusobacterium nucleatum, a pathogen associated with oral plaque formation and colorectal cancers, binds E-cad through its FadA adhesin (Rubinstein et al., 2013). This interaction up-regulates the Annexin A1 and activates β-cat signaling (Zhou et al., 2018; Rubinstein et al., 2019). The F. nucleatum was reported to be associated with a specific epigenetic pattern of tumor cells characterized by hypermethylation of CpG islands, high MSI and MLH1 hypermethylation (epigenetic silencing), and up-regulation of microRNA-21 (Tahara et al., 2014; Yang et al., 2017). Listeria monocytogenes, the causative agent of severe food poisoning, which sometimes lead to meningitis, internalizes when internalin A (InlA) and InlB bind to E-cad and the hepatocyte growth factor receptor on the basolateral surface of epithelial cells (Cossart and Sansonetti, 2004; Barbuddhe and Chakraborty, 2009; Ortega et al., 2017). Streptococcus pneumoniae can cause pneumonia, meningitis, and bacteremia. The flamingo cadherin was reported to serve as receptor for the S. pneumoniae fructose bisphosphate aldolase (Blau et al., 2007), and E-cad was found to act as adherence receptor for the pneumococcal surface adhesin A (PsaA) of S. pneumoniae during the colonization of nasopharyngeal epithelial cells (Anderton et al., 2007). Helicobacter pylori, a bacterium responsible for severe gastric disease, adhere to target cells through interaction with CEACAM cell-surface receptor via its HopQ adhesin (Javaheri et al., 2016). Then, the bacterial HtrA sheddase cleaves the gastric epithelial cell-to-cell junctions through endoproteolysis of E-cad, occludin, and claudin-8 (Tegtmeyer et al., 2017). After transmigration of H. pylori to the basolateral membrane of gastric epithelial cells, the T4SS pilus is activated and injects the CagA cytotoxin into the target cell where the release of β-cat is stimulated (Suzuki et al., 2005; Murata-Kamiya et al., 2007) (Zhao et al., 2018; Tegtmeyer et al., 2019).
In the world of bacteria, other cadherin and CAM play a role during the phase of attachment and invasion (Table 1). The attachment of Leptospira interrogans to host cells was found to be mediated through its interaction with VE-cad, which triggers the process leading to different symptoms, including liver dysfunction, kidney failure, myocarditis, and sometimes the pulmonary hemorrhagic manifestations of leptospirosis (Evangelista et al., 2014). Human host colonization by Haemophilus influenzae began with the binding of the bacteria to I-CAM1 on the surface of the respiratory tract epithelial cells through its Type IV pilus (Tfp), a process leading to respiratory diseases such as cystic fibrosis or chronic obstructive pulmonary disease (Novotny and Bakaletz, 2016). H. influenzae invasion is made even more effective as humans carry adenovirus or respiratory syncytial virus, which are known to increase cell-surface expression of I-CAM1. H. influenzae can also bind CEACAM through outer membrane protein OMP-1 (Tchoupa et al., 2015). CEACAM was also reported to serve as a receptor for the Opa protein of Neisseria gonorrhoeae during the colonization of urogenital mucosal surfaces in humans. It can progress toward acute urethritis with purulent urethral discharge in men, while the infection can remain asymptomatic in women or evolve toward an inflammation of the endocervix or an infection of fallopian tubes (Sintsova et al., 2015).
Table 1
| Bacteria | Receptor(s) | Interaction receptor/pathogen | References |
|---|---|---|---|
| Listeria monocytogenes | E-cadherin | Entry receptor | Bonazzi et al. (2009) |
| Helicobacter pylori | CEA-CAM (E-cadherin) | Induce E-cad cleavage, β-cat signaling | Murata-Kamiya et al. (2007); Hoy et al. (2010); Tegtmeyer et al. (2019) |
| Fusobacterium nucleatum | E-cadherin | Bacteria receptor, β-cat signaling | Rubinstein et al. (2013, 2019); Ma et al. (2018) |
| Bacteroides fragilis | E-cadherin | Bacteria receptor induce E-cad cleavage | Chambers et al. (1997); Obiso et al. (1997) |
| Campylobacter jejuni | E-cadherin | Induce E-cad cleavage, transmigration | Boehm et al. (2015) |
| Streptococcus pneumoniae | E-cadherin, flamingo-CAM | Bacteria adhesion | Anderton et al. (2007) |
| Leptospira interrogans | VE-cadherin | Bacteria adhesion | Evangelista et al. (2014) |
| Haemophilus influenza | ICAM-1, CEA-CAM | Bacteria adhesion | Bookwalter et al. (2008) |
| Haemophilus influenza | ICAM-1, CEA-CAM | Bacteria adhesion | Bookwalter et al. (2008) |
| Neisseria meningitidis | CEA-CAM | Entry receptor | Griffiths et al. (2007) |
| Yersinia pseudotuberculosis | β1-integrin | Bacteria adhesion and internalization | Isberg and Leong (1990) |
Function of E-cad and other CAM molecules in bacteria-mediated infectious diseases.
CAM, cell adhesion molecule; V-CAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule; NCAM, neuronal cell adhesion molecule; CEA-CAM, carcinoembryonic antigen-related cell adhesion molecule.
Besides bacteria, many human pathogens also use E-cad and/or other CAM during the human host colonization, indicating the ubiquitous nature of this process. For example, a fungus, Aspergillus fumigatus, which is responsible for the majority of invasive mold infections in patients undergoing chemotherapy or organ transplantation, was found to bind E-cad and to use it as a receptor for adhesion and endocytosis of blastopores in epithelial cells (Xu et al., 2012; Yan et al., 2015), and Candida albicans, the causative agent of hematogenously disseminated and oropharyngeal candidiasis, internalizes through direct interactions between its surface adhesin Als3 and E-cad on the target cell (Egusa et al., 2005; Phan et al., 2007). Regarding viruses, it has been reported that E-cad, together with claudin 1 and occludin, plays a role in the hepatitis C virus entry into hepatocytes (Colpitts et al., 2016; Li et al., 2016). Several CAM, such as I-CAM, V-CAM, and N-CAM have also been identified as viral receptors for viruses, such as coxsackie A virus; rhinovirus, Enterovirus D68, encephalomyocarditis virus, and rabies virus, respectively (Thoulouze et al., 1998; Bhella, 2015; Wei et al., 2016).
E-Cadherin Degradation Induced by Bacteria During Tissues Invasion and Transmigration
Usually, the commensal microbiota, which supplies the host with molecules essential to life and shapes gene expression in eukaryotic cells (Devaux and Raoult, 2018), together with epithelial cell barriers and appropriate immune responses, efficiently protects the internal body against pathogenic microbial invasion (Abt and Pamer, 2014). Pathogenic bacteria have engineered different strategies to get around these natural defenses by the transcellular route, by acting on cell-to-cell junctions, or by taking advantage of damaged tissues.
Clostridium perfringens, which is the causative agent of gas gangrene and food poisoning, produces a pore-forming delta toxin, which was found capable of reducing cell surface expression of E-cad by enhancing ADAM-10 sheddase activity (Figure 2; Seike et al., 2018). Similarly, the alpha toxin of Staphylococcus aureus binds to and up-regulates ADAM-10 metalloprotease activity in alveolar epithelial cells. This activity results in the cleavage of E-cad and contributes to the pathogenesis of lethal pneumonia (Inoshima et al., 2011). Clostridium botulinum produces the botulinum neurotoxin (BoNT), which provokes flaccid paralysis known as botulism, by inhibiting neurotransmitter release at the neuro-muscular junctions (Carter and Peck, 2015). To allow BoNT complex to pass through the epithelial barrier of the intestinal tract and act on the neurotransmission process, one compound of the BoNT complex termed hemagglutinin (HA), binds E-cad and disrupts the tight junctions (Sugawara and Fujinaga, 2011). The prokaryotic high temperature requirement A (HtrA) protease-mediated cleavage of E-cad that precedes the process of transmigration has been described for gastrointestinal pathogens, such as enteropathogenic Escherichia coli, Shigella flexneri, and Campylobacter jejuni (Boehm et al., 2012; Hoy et al., 2012; Elmi et al., 2016). The HtrA sheddase of Helicobacter pylori was found to open adherens junctions by cleaving E-cad and claudin-8 occludin (Tegtmeyer et al., 2017). HtrA sheddase has been found in most of the bacterial genomes studied to date and is associated with pathogenicity. An opportunistic pathogen like Serratia marcescens produces a pore-forming toxin (ShlA) responsible for the tissues damage required to cross cellular barriers (Hertle and Schwarz, 2004). Another opportunistic bacterium, Pseudomonas aeruginosa, which causes aggressive infections in patients compromised by respiratory diseases such as cystic fibrosis, also encodes a pore-forming toxin (exolysin A) that induces major injuries of tissues (Reboud et al., 2017). Both SHlA and ExlA influence ADAM-10 activation triggering E-cad and VE-cad cleavage in epithelial and endothelial cells, respectively, as well as soluble CAMs shedding, and intercellular junction rupture (Reboud et al., 2017). Leptospira interrogans, which crosses host tissue barriers and causes leptospirosis, secretes a protein named LIC10831 that binds E-cad and VE-cad and plays a role during bacterial invasion (Eshghi et al., 2019). The genome of Porphyromonas gingivalis, a bacterium associated with adult periodontitis (Katz et al., 2000), encodes three cysteine proteases named Gingipains (HRgpA, RgpB, and Kgp). The Kgp protease was found capable to disrupt adherens junction by cleavage of E-cad (Katz, 2002). P. gingivalis also cleaves N- and VE-cads (Sheets et al., 2005). With the L. monocytogenes, the infectious process starts with the interaction between the invasion proteins internalin and InlB and their cellular receptor E-cad and hepatocyte growth factor receptor (HGF-R)/Met (Seveau et al., 2004). E-cad also constitutes a target for L. monocytogenes in order to disrupt the blood brain barrier and facilitate the invasion of the brain (Al-Obaidi and Desa, 2018). In Chlamydia trachomatis infections, a bacterium responsible for acute salpingitis and cervicitis, which can also induce scarring disease of the ocular mucosa, a DNA methylation of the CDH1 promoter and downregulation of E-cad expression, was reported (Rajić et al., 2017). It can be hypothesized that the list of pathogenic bacteria shown to cleave the E-cad during the invasion process will increase rapidly.
Figure 2
For other pathogens, such a requirement to achieve transmigration for colonizing their host can also be illustrated with a few examples. Tissues invasion by C. albicans is associated with degradation of E-cad mediated by the fungus aspartyl proteinase Sap5p under the control of the transcription factor Rim101p (Villar et al., 2007). C. albicans was also reported capable of reducing E-cad mRNA expression (Rouabhia et al., 2012). More recently, it was reported that C. albicans synergized with Streptococcus oralis to increase the proteolytic degradation of E-cad by μ-calpain, which facilitates fungal invasion (Xu et al., 2016). It illustrates the fact that the modulation of cell-surface expression of E-cad is not limited to bacteria, but is rather a general mechanism used by infectious pathogens for invasion and transmigration (Grabowska and Day, 2012).
Proteolytic Cleavage of E-Cadherin by Eukaryotic Sheddases
As described above in this paper, pathogenic bacteria such as H. pylori, Pseudomonas aeruginosa, Serratia marcescens, Clostridium perfringens, and S. aureus have developed takeover stratagems to use eukaryotic sheddases of the human host (e.g., ADAM-10) in order to modulate the host cell surface expression of E-cad.
The cleavage of adhesion molecules is far from being limited to the pathogens' invasion processes. Apart dysbiosis, proteolysis is a common physiological mechanism of post-translational regulation that affects 2–4% of the proteins expressed on the surface of cells (Pandiella et al., 1992; Arribas and Merlos-Suárez, 2003). E-cad is one of the molecules that can undergo proteolytic cleavage (both intracellular and extracellular), providing an alternative regulatory mechanism to reduce its cell surface expression (Noë et al., 2001; Marambaud, 2002; van Roy and Berx, 2008). It is essential to regulate the balance between adhesion and migration of cells. The human genome encodes almost 600 proteases, which control a wide range of processes essential to life (Turk et al., 2012). Proteases can be organized into five main classes, including cysteine proteases, serine proteases, metalloproteases, threonine proteases, and aspartic proteases, with approximately one half being extracellular and the other half intracellular. Quantitative cell surface expression of E-cad is therefore determined by the balance between biosynthesis, trafficking, transfer to cell-surface, intracellular and extracellular proteolytic cleavage, and intracellular degradation, and these processes are considered crucial determinants for cell behavior (Godt and Tepass, 1998). Endoproteases (which cleave internal peptides bonds), which are capable of extracellular E-cad cleavage, belong to the large family of sheddases (Grabowska and Day, 2012). The human sheddases (Figure 3) include zinc-dependent matrix metalloproteases (matrilysin/MMP-2, 3, 7, 9, and 14) (Lee et al., 2007; Symowicz et al., 2007; Klein and Bischoff, 2011), members of the disintegrin metalloproteases family (adamalysin/ADAM-10 and -15) (Maretzky et al., 2008; Najy et al., 2008; Giebeler and Zigrino, 2016), cysteine cathepsins (B, L, S) (Jordans et al., 2009), serine protease kallikrein (KLK-6 and -7) (Johnson et al., 2007; Klucky et al., 2007), plasmin serine protease (Ryniers et al., 2002), and the membrane-bound aspartic proteinases BACE-1 and BACE-2 (Wakabayashi and De Strooper, 2008; Grabowska and Day, 2012). Sheddases are secreted as proenzymes and become mature after processing of the propeptide; for example, the matrix metalloprotease 3 is synthesized as a zymogen (proMMP-3) which is converted to full activity (two active forms of 45-kDa and 25-kDa) by limited proteolysis mediated by elastase and cathepsin G (Okada and Nakanishi, 1989; Becker et al., 1995). Similarly, the MMP-9 is synthesized as a 92-kDa proMMP-9, and then the active MMP-3 initially cleaves proMMP-9 to generate a 86-kDa intermediate ultimately cleaved to convert the intermediate form into a 82-kDa catalytic form (Ogata et al., 1992). The catalytic domains of MMP-9 alone can hydrolyze non-collagenous proteins and synthetic substrates, but cannot cleave triple helix collagens without the hemopexin domain (Nagase et al., 2006). Its fibronectin type II domains are important to cleave type IV collagen, elastin, and gelatins. The hemopexin domain is required for collagenolytic activity of the collagenase. The catalytic activity of sheddases triggers the extracellular release of a soluble E-cad (sE-cad) fragment of about 80-kDa from the cell surface. This process is accompanied by the simultaneous delivery of free β-cat into the cell cytosol, which then translocates into the cell nucleus where it contributes to the modulation of gene expression. It is worth noting that sE-cad might also behave as a signaling molecule through ErbB receptor activation (Najy et al., 2008). As already mentioned above, some pathogenic bacteria can enslave eukaryotic sheddase to get E-cad cleaved.
Figure 3
Inactivation of the CDH1 Gene by Methylation is Associated With Pre-carcinogenic Programming During Pathogenic Bacteria Invasion
Several pathogenic bacteria were found to control the CDH1 gene expression at the chromatin level through activation of signaling cascade leading to modulation of DNA-binding proteins or directly in the nucleus through epigenetic modifications (Bierne et al., 2012). Inactivation of the CDH1 gene leads to the down-modulates of E-cad protein expression.
It was reported that methylation of the CDH1 gene promoter is a frequent event in samples from H. pylori infected patients with chronic gastritis, suggesting that CDH1 inactivation is an early step toward gastric tumorigenesis (Kague et al., 2010). Methylation of the CDH1 gene promoter was also reported in about 30–40% of patients with H. pylori-associated gastric carcinoma (Bahnassy et al., 2018). The CDH1 promoter methylation was reduced after H. pylori eradication (Perri et al., 2007). Chlamydia trachomatis infection inducing scarring disease of the ocular mucosa was found to be associated with CDH1 promoter DNA methylation and down-regulation of E-cad (Rajić et al., 2017). Acinetobacter baumannii is an opportunistic pathogen causing severe diseases in patients with mechanical ventilation. The nuclear targeting of Acinetobacter baumannii transposase (Tnp) induces DNA methylation of CpG regions in the promoter of the CDH1 gene resulting in down-regulation of gene expression (Moon et al., 2012). To date, the CDH1 gene inactivation has not been systematically explored for pathogenic bacteria and should be questioned as part of the exploration of the molecular mechanisms by which pathogenic bacteria deregulate E-cad expression to colonize the human host.
The epigenetic modulation of the CDH1 gene during pathogenic bacteria infection mimics processes well-described in the studies regarding the embryologic development. Repression of the CDH1 gene and cad-switching from E-cad to N-cad were considered essential for transitioning away from pluripotency (Sauka-Spengler and Bronner-Fraser, 2008; Li et al., 2010; Pieters and van Roy, 2014). Such cad-switching (Thiery, 2002) as well as reduced expression of E-cad have also been observed in cancer cases (including breast cancer, gastric cancer, colorectal cancer, and hepatocellular carcinomas), indicating that inhibition of E-cad surface expression can play a central role in the progression toward cancer (Jeanes et al., 2008; Gall and Frampton, 2013). However, in lung cancer cells, E-cad was found induced by WNT7a (Ohira et al., 2003), and E-cad expression is increased in both ovarian cancer malignant effusions and solid metastases (Davidson et al., 2000; Elloul et al., 2006). E-cad is generally considered a tumor suppressor through inhibition of β-cat nuclear translocation (Gottardi et al., 2001) and can act as oncogene through binding to EGFR/Erb receptor that triggers ERK and AKT signaling pathways providing advantage for cancer development and metastasis (Wells et al., 2008; Rodriguez et al., 2012).
With regard to viruses as examples of other pathogens modulating CDH1 gene expression, it has been reported that hepatitis B virus (HBV) represses E-cad at the transcriptional level by hypermethylation of the CDH1 promoter on CpG Island 1 with possible consequences on hepatocellular carcinogenesis by promoting detachment of surrounding cells and their migration to the primary tumor site (Lee et al., 2005). Alternatively, loss of E-cad in HBV infected cells can also be regulated at a post-translational level by proteases and SUMOylation (Ha et al., 2016). Hypermethylation that triggers CDH-1 gene repression was also found with the human papillomavirus (HPV) that increases cellular methyltransferase 1 (Dnmt1) activity via its viral E7 protein (Laurson et al., 2010).
Aberrant Splicing of the E-Cadherin Transcript
Among the gene silencing molecular mechanisms underlying E-cad loss, one involves the expression of nonfunctional truncated CDH1 gene transcript. E-cadherin mRNA with premature termination codon mutation was reported in chronic lymphocytic leukemia cells (Sharma and Lichtenstein, 2009). This transcript (which lacks the exon 11) plays a role in silencing the production of E-cad. The amounts of wild-type E-cad mRNA inversely correlated with the amounts of aberrant transcript resulting in the up-regulation of the Wnt-β catenin pathway. The production of E-cad mRNA variant by alternative splicing has also been linked to a decrease in cell-cell adhesion and an increase in cell migration (Matos et al., 2017). The novel E-cadherin variant, a truncated soluble form of E-cad resulting from a deletion of the first 34 nt in the exon 14 of the CDH1 mRNA, induces changes characteristic of the Epithelial to Mesenchymal Transition (EMT) process, a key event in tumor progression (Matos et al., 2017). Moreover, the over-expression of this novel E-cad truncated form in transfected cells resulted in downregulation of wild-type E-cad expression. This truncated CDH1 gene transcript was recently found in breast cancer cells (Rosso et al., 2019). Aberrant splicing of CDH1 gene transcript (exon 8 or exon 11 skipped aberrant transcripts) was also reported in gastric carcinoma (Garziera et al., 2013; Li et al., 2015). Although this is a possibility, it has not yet been demonstrated that the expression of a CDH1 aberrant transcript in gastric cancers is controlled by H. pylori. However, it is known that aberrant splicing of cellular gene transcripts can occur during bacterial invasion (Sun, 2017). Indeed, massive alterations in the pattern of cellular mRNA splicing were reported upon infection with bacteria such as Anaplasma phagocytophilum, the etiologic agent of the human granulocytic anaplasmosis (Dumler et al., 2018) and Mycobacterium tuberculosis the etiologic agent of tuberculosis (Kalam et al., 2018). This may be consistent with the observation that Mycobacterium tuberculosis induced an epithelial mesenchymal transition in a pulmonary adenocarcinoma epithelial cell line (Gupta et al., 2016), a phenomenon orchestrated at the level of E-cad cell-surface expression. It was also reported that the EMT of mesothelial cells occurred in Mycobacterium tuberculosis-associated pleurisy, together with a reduction in E-cad expression (Kim et al., 2011). Moreover, expression level of E-cad was reported to differ between pulmonary tuberculosis patients and latent tuberculosis individuals (Sun et al., 2018).
Release of Soluble E-Cadherin After Bacterial Infection as an Early Event Toward Carcinogenesis
Aside from the transcriptional repression of the CDH1 gene, another interesting mechanism, which could interfere with the anti-bacterial defenses of the host, is the release of sE-cad in body fluids following a sheddase-mediated cleavage of E-cad. The combination of sE-cad release together with other pro-inflammatory factors was highlighted as a triggering signal that promotes gastric adenocarcinoma or colorectal tumors in patients infected with H. pylori, B. fragilis, or Streptococcus gallolyticus (Wu et al., 2003; O’Connor et al., 2011; Kumar et al., 2017; Chung et al., 2018).
H. pylori, a bacterium that colonizes the gastric mucosa, is known as a risk factor for the development of chronic atrophic gastritis, gastroduodenal ulcers, and adenocarcinoma. An in vitro experimental model of cell transfection has demonstrated that H. pylori triggers β-cat activation through the interaction of virulence factor CagA with E-cad (Murata-Kamiya et al., 2007). O’Connor et al. (2011) reported that H. pylori induced the activation of host protease calpain via the toll-like receptor 2 (TLR2) and disruption of gastric epithelium. Another report suggests that ADAM-10 is induced in H. pylori infection and contributes to the shedding of E-cad (Schirrmeister et al., 2009). It was also reported that a serine protease HtrA from H. pylori mediate direct cleavage of E-cad (Hoy et al., 2010; Schmidt et al., 2016). Bacterium S. gallolyticus has a strong association with colorectal cancer with increased levels of β-cat and c-Myc (Kumar et al., 2017). The genome of another bacterium, Bacteroides fragilis, encodes a sheddase, the B. fragilis toxin (BFT) also termed fragilis (FRA), which cleaves E-cad and is associated with C-Myc expression and cellular proliferation (Wu et al., 1998, 2003; Remacle et al., 2014; Chung et al., 2018). Chung and co-workers uncovered a complex mechanism whereby the B. fragilis toxin (BFT)-mediated cleavage of E-cad initiates a multi-step inflammatory cascade requiring β-cat, IL-17R, NF-B, and Stat3 signaling in colonic epithelial cells. IL-17 dependent NF-κB activation in colic epithelial cells induces a mucosal gradient of C-X-C chemokines that initiates pro-tumoral myeloid cell infiltration to the distal colon and colon cancer. All these cancers are solid tumors. However, a role for sE-cad in the initiation of a pro-carcinogenic process might also be considered. Over the past 3 years, we have reported results suggesting that the bacterium Coxiella burnetii, responsible of Q fever, was associated with a higher frequency of Non-Hodgkin Lymphoma (NHL) in C. burnetii-infected patients compared to the general population (Melenotte et al., 2016). Recently, we investigated the transcriptional signature that could be associated with the development of NHL in Q fever patients and found an over-expression of genes involved in anti-apoptotic process and a repression of pro-apoptotic genes (Melenotte et al., 2019). Since cell surface expression of E-cad and release of sE-cad have been associated to various pathogenic bacteria known for inducing solid tumors, we have also investigated the levels of expression of these molecules in Q fever patients and observed a significant release of sE-cad in their sera and a down-regulation of E-cad mRNA expression. The sE-cad levels were found increased in the sera of acute and persistent Q fever patients, whereas they remained at the baseline in the control groups of healthy donors, people cured of Q fever, patients suffering from unrelated inflammatory diseases, and past Q fever patients who developed NHL (Table 2). Consequently, sE-cad could be considered a new biomarker of C. burnetii infection rather than a marker of NHL-associated to Q fever (Mezouar et al., 2019). We do not yet know which eukaryotic or prokaryotic sheddase could be responsible for the cleavage of E-cad in patients infected with C. burnetii. Preliminary studies on peripheral blood mononuclear cells exposed to heat-inactivated C. burnetii suggested variations in ADAM-10 and MMP-9 expression. Microarray performed on samples from macrophages and dendritic cells (DC) infected in vitro by C. burnetii revealed an over-expression of MMP-3 in C. burnetii-infected DC. Preliminary investigations in search of sheddase have also been conducted. We tried to blast the protein sequences of more than 20 sheddases known to catalyze the cleavage of E-cad against the hypothetical proteins of four strains of C. burnetii. We found that three eukaryotic sheddases (MMP-3, MMP-9, and ADAM-15) presented sequence similarities with bacterial proteins. Experiments are under progress to identify whether an ADAM or MMP eukaryotic protease or a prokaryotic protease encoded by C. burnetii could be responsible for sE-cad release in Q fever patients.
Table 2
| Pathogens | Sample/Technic | Cadherin | Results | References |
|---|---|---|---|---|
| C. burnetii | Plasma/Elisa | sE-cadherin | Increased in infected patients including acute and persistent forms of the disease | Mezouar et al. (2019) |
| H. pylori | Serum/Elisa | sE-cadherin | Increased in positive H. pylori patients | O’Connor et al. (2011) |
| E. coli (Shiga toxin 2 from) | Plasma/Elisa | VE-cadherin | Increased in infected patients | Doulgere et al. (2015) |
Soluble Cad molecules released in body fluids during bacteria-associated infectious diseases.
If the general trend is to increase the soluble forms of cadherin molecules in body fluids of patients infected with pathogenic bacteria, caution should be exercised when comparing results obtained with different diagnostic kits, in different laboratories and with serum or plasma samples. Regarding the results reported in the papers mentioned in this table, the concentrations of soluble Cad measured in the samples were two times higher in the infected patients than in healthy controls. For example, in the plasma of C. burnetii-infected patients, the sE-cad concentration was about 170–450 ng/ml in acute Q fever (median 272 ng/ml), 260–530 ng/ml in persistent Q fever (median 333 ng/ml), while it was 80–320 ng/ml (median 164 ng/ml) in healthy controls.
Care must be taken not to overinterpret the significance of sE-cad increase in body fluids during bacterial infections. It is possible that sE-cad release in body fluids corresponds to a ubiquitous phenomenon induced during the process of colonization of the host by a pathogenic bacterium. We already know that it is not limited to bacteria since there is an apparent correlation between the levels of sE-cad in human immunodeficiency virus (HIV)-positive patients and their viral titers (Streeck et al., 2011). Moreover, abnormal concentrations of sE-cad in patients’ sera has been observed in several metabolic and inflammatory diseases (Pittard et al., 1996; Jiang et al., 2009; Shirahata et al., 2018; Sato et al., 2019). High concentration of sE-cad has also been found associated with cancer progression (Grabowska and Day, 2012; Salama et al., 2013; Repetto et al., 2014). For example, high concentration of sE-cad was described in prostate cancer patients and was associated with an over-expression of MMP-2 and MMP-9 (Kuefer et al., 2005; Biswas et al., 2010; Tsaur et al., 2015). Similarly, increased expression of sE-cad was reported in gastric cancer that was associated with the over-expression of MMP-7 (Lee et al., 2006, 2007). Serum levels of sE-cad were increased in patients with ovarian carcinoma the cleavage of E-cad being mediated by MMP-9 (Gadducci et al., 1999; Symowicz et al., 2007). Altogether, these data suggest that high sE-cad concentration in body fluids could simply behave as a factor that predisposes to inflammation and development of cancers, as described for H. pylori-infected patients.
Dysfunction of the Immune Response Orchestrated by Bacteria-Induced E-Cadherin Cleavage
The immune system naturally provides an anti-infectious surveillance at the epithelium level via cells that express cell-surface molecules, such as CD103 and KLRG1, able to bind the E-cad found at the surface of epithelial cells. These immune cells are not heavily engaged, unless the other defenses have failed. For example, under normal conditions, the intestinal epithelium is protected by a mucus layer that acts as host defense against microbial attachment (Kim and Ho, 2010; Desai et al., 2016). Upon infection, the specialized intestinal Paneth cells secretes antimicrobial proteins and the commensal intestinal microbiota competes with the infectious pathogens, thereby acting as first line of innate defense to fight against pathogenic bacteria (Cash et al., 2006; Mason and Huffnagle, 2009; Vazeille et al., 2011; Bel et al., 2017). The epithelium integrity controlled by the homotypic interaction of E-cad in trans represents a second barrier protecting the host against intruder transmigration (Kim et al., 2010). When pathogenic bacteria had evaded epithelial cell autophagic clearance and dead cells renewal (Yoshikawa et al., 2009; Benjamin et al., 2013), the host’s immune system represents the last rampart before the pathogens can breach the epithelium and disseminate deeper.
The intestinal villous microfold cells (M cells) are specialized epithelial cells of the gut-associated lymphoid tissues (GALT) that deliver luminal antigens to the underlying immune system after their transport to the basolateral membrane of M cells (Miller et al., 2007). An efficient immune response against a microbial attack requires the migration of cells of the host immune system in the microenvironment where infection occurs and the sequential detection of stress signals, tissue damages and conserved bacterial molecules termed pathogen-associated molecular patterns (PAMPs) (Broz and Monack, 2013). PAMPS include molecules as diverse as lipopolysaccharide, flagellin, peptidoglycan, lipoproteins, and unique bacterial nucleic acid structures. Upon detection of bacterial invasion, host cell receptors such as toll-like receptors and C-type lectin receptors, activate signaling pathways that govern the production of inflammatory cytokines including the IL-1β and IL-18 that can restrict bacterial replication. Causative agents of infectious diseases are therefore characterized by their capacity to elaborate mechanisms aimed to damage the protective cellular barriers and/or to modulate immune responses of the host to achieve invasion.
We can question the place of the E-cad in this process of mobilization of immunity cells via trans homotypic (e.g., E-cad) or trans heterotypic (e.g., CD103 and KLRG1) interactions under normal and pathological conditions (Figure 4). Although E-cad is expressed by immature CD4+CD8+ thymocytes (Munro et al., 1996; Müller et al., 1997), after the thymocytes have left the thymus, E-cad is generally absent from most mature lymphocytes (Lee et al., 1994). Yet, under certain pathological conditions, cell-surface expression of E-cad was reported on mature T-lymphocytes (CD3+) subsets, as well as B cells (CD19+), NK cells (DX5+), and monocyte/macrophages (CD11b+) subpopulations (Esch et al., 2000; Sakai et al., 2008). E-cad expression was also confirmed for subpopulations of epithelial γδ T-cells (Lee et al., 1994) and memory CD8+ T-cells in intestinal mucosa (Hofmann and Pircher, 2011). Moreover, we have recently observed that 30% of CD16+ monocytes expressed E-cad after C. burnetii infection (Mezouar et al., 2019). In the intestinal epithelium, it is generally accepted that the immune host defense is mainly mediated by effector cells that express the αE integrin (CD103), an E-cad ligand (Banh and Brossay, 2009; Van den Bossche et al., 2012). CD103 is expressed on 40–50% of CD4+ T-lymphocytes and 90% of CD8+ T-lymphocytes that reside in the intestinal mucosa as well as on the surface of intraepithelial lymphocytes (Cerf-Bensussan et al., 1987; Kilshaw and Murant, 1990; Hadley et al., 1997; Uchida et al., 2011). It is also present on T cells of the intestinal lamina propria (Agace et al., 2000) and a subset of CD4+CD25+ Foxp3+ Treg-cells (Stephens et al., 2007). It was demonstrated that after epithelial damages, the intraepithelial CD103+ γδ T-lymphocytes that reside on the surface of epithelium promote mucosal repair through antibacterial factors (e.g., Reg3γ) and immunomodulatory molecules (e.g., IL1β, CXCL9) (Cepek et al., 1994; Ismail et al., 2009, 2011). It is worth noting that the intestinal CD103+ intraepithelial lymphocytes adherence to epithelial cells is inhibited by antibodies against CD103 (Cepek et al., 1993). Another cell-surface receptor named KLRG1 that is encountered on subsets of immune cells including mature NK cells, memory CD4+T cells, effector CD8+ T cells, and FoxP3+ Treg cells, is known to bind E-cad (Schwartzkopff et al., 2007; Tessmer et al., 2007; Banh and Brossay, 2009; Van den Bossche et al., 2012). It has been reported that high levels of sE-cad could be sufficient to inhibit CD8+ T-cell function in a KLRG1-dependent manner (Streeck et al., 2011).
Figure 4
The E-cad induction on subpopulations of immune response cells in pathological situations remain to be elucidated. It can be hypothesized that the aberrant expression of E-cad under pathological conditions reflects changes in the transmigration and homing capacity of these cells (Reyat et al., 2017). Because several pathogenic bacteria reduce the epithelium surface expression of E-cad at the site of infection, it might be speculated that the decreased expression or the lack of expression of E-cad on epithelial cells is likely to trigger the rerouting of immune cells far from the infection site. As previously shown by Streeck et al. (2011) for the KLRG1+ CD8+ T-cells subpopulation, the release of sE-cad might also serve as a decoy for diverting from their function the immune cells expressing E-cad, CD103 or KLRG1 after engagement of such receptors with sE-cad. Modulation of E-cad expression on the host epithelial cells and sE-cad release could therefore be considered a very efficient stratagem to prevent the immune system from behaving as a line of defense against invaders. In addition, for bacteria that induce cancer, reducing the expression of E-cad on certain tumor cells as previously reported (Shields et al., 2019) and disrupting the migration and attachment capabilities of immune survey cells could be a way of promoting the development of bacteria-induced cancers.
Conclusion and Discussion
This review highlights how the E-cad can be diverted from its function of maintenance of tissues integrity and prevention of cell migration/differentiation during pathogenic bacterial infections. Pathogenic bacteria can use E-cad for their attachment to epithelial cells. Indeed, they can cleave E-cad to ensure their transmigration and can modulate the responsiveness of immune cells through modulation of cell-surface expression of E-cad and sE-cad release in body fluids. Some bacteria use E-cad to enter their target cells (e.g., F. nucleatum, L. monocytogenes, S. pneumoniae). Several bacteria act on the cell-surface expression of this molecule, either by modulating the CDH1 gene transcription (e.g., C. trachomatis, H. pylori) or by inducing the cleavage of the E-cad molecule (e.g., C. perfringens, S. aureus, C. burnetii) via proteases (sheddases). This process can favor achievement of the trans-epithelial host invasion or modulate host-pathogen molecular crosstalk. Currently, the best studied models are those that refer to intestinal infections that can lead to cancer (Figure 5).
Figure 5
Proteases (cysteine proteases, serine proteases, aspartate proteases, and metalloproteases) are ubiquitously encountered in the microbial world and are essential for their survival and replication cycle (Häse and Finkelstein, 1993). Proteases, such as collagenase (Bond and Van Wart, 1984), elastase (Bever and Iglewski, 1988), or metalloprotease (Schiavo et al., 1992) (Domann et al., 1992) were associated with bacterial pathogenesis. Some pathogenic bacteria can activate the production of eukaryotic proteases such as ADAM-10 via signaling (e.g., this was reported for P. aeruginosa, S. marcescens, C. perfringens, S. aureus), whereas others use a portion of their genome to encode their own sheddase, including the HtrA protease (encoded by H. pylori, C. jejuni, S. flexneri, enteropathogenic E. coli) or B. fragilis toxin (encoded by B. fragilis).
As described above in this paper, evidence emphasizing that cleavage of E-cad by sheddases and release of sE-cad into the body fluids are factors that contribute to the progression of cancer (sometimes it was demonstrated). Within the group of bacteria that modulate the expression of E-cad, the association with carcinogenic processes has been investigated, in particular with H. pylori, F. nucleatum, S. gallolyticus, and B. fragilis. H. pylori is known to be a risk factor for the development of gastric adenocarcinoma and the progression toward cancer is likely related to E-cad cleavage and β-cat activation (Murata-Kamiya et al., 2007), F. nucleatum promotes colorectal cancer by modulating the E-cad and Wnt/β-cat signaling via its FadA adhesin and up-regulating annexin A1 (Rubinstein et al., 2013, 2019). S. gallolyticus is also associated with colorectal cancer with known increased level of β-cat and c-Myc activation (Kumar et al., 2017). B. fragilis toxin (BFT)-mediated cleavage of E-cad initiates a multi-step inflammatory cascade requiring β-cat nuclear translocation, activation of NF-κB and Stat3 signaling pathways in colonic epithelial cells as early events leading to pro-tumoral myeloid cell infiltration to the distal colon and colon cancer (Chung et al., 2018). Our recent data indicate that C. burnetii, reported as associated with occurrence of non-Hodgkin lymphoma, is also capable of triggering cleavage of E-cad and release of sE-cad in the sera of Q fever patients (Figure 6; Mezouar et al., 2019). Yet, further experiments are required to formerly demonstrate the association between sE-cad release in sera from Q fever patients and the initiation of a pro-carcinogenic inflammatory process leading to lymphoma development.
Figure 6
The accumulation of data showing that sE-cad is produced in many pathological processes that can lead to cancer development raises the question of what value can be attributed to this compound as a biomarker of disease severity. At the moment, we do not have enough information to conclude. The presence of sE-cad in body fluids was considered a possible biomarker in H. pylori (O’Connor et al., 2011) and C. burnetii (Mezouar et al., 2019) infections, and soluble VE-cad was also regarded as possible biomarker in E. coli infections (Doulgere et al., 2015). We are currently implementing a test protocol to assess whether sE-cad could be a biomarker for tuberculosis and severe C. difficile infections. CD68+ granuloma macrophages from M. tuberculosis patients were reported to express E-cad (Cronan et al., 2016). Moreover, using M. marinum as model, Cronan and collaborators reported that the mycobacterial granuloma formation is accompanied by macrophage reprogramming that parallels E-cad-dependent mesenchymal-epithelial transitions and alters immune response. E-cadherin induction was found in the granuloma of both M. marinum-infected and uninfected granuloma macrophages, while macrophages residing outside the granuloma remained negative for E-cad. Concerning C. difficile, the etiologic agent of pseudomembranous colitis and severe diarrhea, it was reported that C. difficile TcdB toxin induces the redistribution of occludin and ZO-1without influencing the subjacent E-cad (Nusrat et al., 2001).
For the management of H. pylori gastrointestinal disorders and H. pylori-associated gastric cancer, it is recommended to use a combination of ranitidine bismuth citrate, clarithromycin, and amoxicillin (Goderska et al., 2018). In a near future, it will not be surprising to consider the possibility of proposing therapeutic approaches that will combine antibiotics, probiotics, and sheddase inhibitors to regulate E-cad as well as β-cat inhibitors. Probiotics (e.g., the yeast Saccharomyces boulardii CNCMI-745) have been used to restore intestinal barrier integrity in patients with inflammatory bowel disease, by regulation of E-cad recycling (Terciolo et al., 2017). Intensive research is aimed at developing inhibitors of MMPs (Antczak et al., 2008; Tuccinardi et al., 2008; Schmidt et al., 2016; Katoh, 2017) and ADAMs (Madoux et al., 2016). MMP-9 inhibitors that abrogate E-cad cleavage are considered a promising tool for therapeutic of colorectal cancers (Biswas et al., 2010; Marshall et al., 2015). This opens up new avenues of research for therapeutic purposes.
Statements
Author contributions
CD, SM and J-LM conceived the paper. SM and CD designed the tables and figures. CD wrote the paper.
Funding
SM was first supported by a “Fondation pour la Recherche Médicale” postdoctoral fellowship (reference: SPF20151234951) and then by the “Fondation Méditerranée Infection”. This work was supported by the French Government under the “Investissements d’avenir” (Investments for the Future) program managed by the “Agence Nationale de la Recherche” (reference: Méditerranée Infection 10-IAHU-03). Art supply of images available under a Creative Commons CCBY 3.0 license.
Acknowledgments
We thank Magdalen Lardière for English editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AbtM. C.PamerE. G. (2014). Commensal bacteria mediated defenses against pathogens. Curr. Opin. Immunol.29, 16–22. doi: 10.1016/j.coi.2014.03.003
2
AgaceW. W.HigginsJ. M.SadasivanB.BrennerM. B.ParkerC. M. (2000). T-lymphocyte-epithelial-cell interactions: integrin alpha(E)(CD103)beta(7), LEEP-CAM and chemokines. Curr. Opin. Cell Biol.12, 563–568. doi: 10.1016/S0955-0674(00)00132-0
3
Al-ObaidiM. M. J.DesaM. N. M. (2018). Mechanisms of blood brain barrier disruption by different types of bacteria, and bacterial-host interactions facilitate the bacterial pathogen invading the brain. Cell. Mol. Neurobiol.38, 1349–1368. doi: 10.1007/s10571-018-0609-2
4
AndertonJ. M.RajamG.Romero-SteinerS.SummerS.KowalczykA. P.CarloneG. M.et al. (2007). E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb. Pathog.42, 225–236. doi: 10.1016/j.micpath.2007.02.003
5
AngstB. D.MarcozziC.MageeA. I. (2001). The cadherin superfamily: diversity in form and function. J. Cell Sci.114, 629–641. PMID:
6
AntczakC.RaduC.DjaballahH. (2008). A profiling platform for the identification of selective metalloprotease inhibitors. J. Biomol. Screen.13, 285–294. doi: 10.1177/1087057108315877
7
ArribasJ.Merlos-SuárezA. (2003). Shedding of plasma membrane proteins. Curr. Top. Dev. Biol.54, 125–144.
8
BahnassyA. A.HelalT. E.-A.El-GhazawyI. M.SamaanG. F.Galal El-DinM. M.AbdellateifM. S.et al. (2018). The role of E-cadherin and Runx3 in Helicobacter pylori-associated gastric carcinoma is achieved through regulating P21waf and P27 expression. Cancer Genet.228–229, 64–72. doi: 10.1016/j.cancergen.2018.08.006
9
BanhC.BrossayL. (2009). Immune receptors, cadherins and their interactions. Curr. Immunol. Rev.5, 2–9. doi: 10.2174/157339509787314440
10
BarbuddheS. B.ChakrabortyT. (2009). Listeria as an enteroinvasive gastrointestinal pathogen. Curr. Top. Microbiol. Immunol.337, 173–195. doi: 10.1007/978-3-642-01846-6_6
11
BarkerN.HurlstoneA.MusisiH.MilesA.BienzM.CleversH. (2001). The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J.20, 4935–4943. doi: 10.1093/emboj/20.17.4935
12
BeckerJ. W.MarcyA. I.RokoszL. L.AxelM. G.BurbaumJ. J.FitzgeraldP. M.et al. (1995). Stromelysin-1: three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Protein Sci.4, 1966–1976. doi: 10.1002/pro.5560041002
13
BelS.PendseM.WangY.LiY.RuhnK. A.HassellB.et al. (2017). Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science357, 1047–1052. doi: 10.1126/science.aal4677
14
BenjaminJ. L.SumpterR.LevineB.HooperL. V. (2013). Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe13, 723–734. doi: 10.1016/j.chom.2013.05.004
15
BerxG.BeckerK. F.HöflerH.van RoyF. (1998). Mutations of the human E-cadherin (CDH1) gene. Hum. Mutat.12, 226–237. doi: 10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D
16
BerxG.StaesK.van HengelJ.MolemansF.BussemakersM. J.van BokhovenA.et al. (1995). Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1). Genomics26, 281–289. doi: 10.1016/0888-7543(95)80212-5
17
BeverR. A.IglewskiB. H. (1988). Molecular characterization and nucleotide sequence of the Pseudomonas aeruginosa elastase structural gene. J. Bacteriol.170, 4309–4314. doi: 10.1128/jb.170.9.4309-4314.1988
18
BhellaD. (2015). The role of cellular adhesion molecules in virus attachment and entry. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci.370:20140035. doi: 10.1098/rstb.2014.0035
19
BierneH.TravierL.MahlakõivT.TailleuxL.SubtilA.LebretonA.et al. (2012). Activation of type III interferon genes by pathogenic bacteria in infected epithelial cells and mouse placenta. PLoS One7:e39080. doi: 10.1371/journal.pone.0039080
20
BiswasM. H. U.DuC.ZhangC.StraubhaarJ.LanguinoL. R.BalajiK. C. (2010). Protein kinase D1 inhibits cell proliferation through matrix metalloproteinase-2 and matrix metalloproteinase-9 secretion in prostate cancer. Cancer Res.70, 2095–2104. doi: 10.1158/0008-5472.CAN-09-4155
21
BlauK.PortnoiM.ShaganM.KaganovichA.RomS.KafkaD.et al. (2007). Flamingo cadherin: a putative host receptor for Streptococcus pneumoniae. J. Infect. Dis.195, 1828–1837. doi: 10.1086/518038
22
BoehmM.HoyB.RohdeM.TegtmeyerN.BækK. T.OyarzabalO. A.et al. (2012). Rapid paracellular transmigration of Campylobacter jejuni across polarized epithelial cells without affecting TER: role of proteolytic-active HtrA cleaving E-cadherin but not fibronectin. Gut Pathog.4:3. doi: 10.1186/1757-4749-4-3
23
BoehmM.LindJ.BackertS.TegtmeyerN. (2015). Campylobacter jejuni serine protease HtrA plays an important role in heat tolerance, oxygen resistance, host cell adhesion, invasion, and transmigration. Eur. J. Microbiol. Immunol.5, 68–80. doi: 10.1556/EuJMI-D-15-00003
24
BoggonT. J. (2002). C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science296, 1308–1313. doi: 10.1126/science.1071559
25
BolósV.PeinadoH.Pérez-MorenoM. A.FragaM. F.EstellerM.CanoA. (2003). The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with snail and E47 repressors. J. Cell Sci.116, 499–511. doi: 10.1242/jcs.00224
26
BonazziM.LecuitM.CossartP. (2009). Listeria monocytogenes internalin and E-cadherin: from bench to bedside. Cold Spring Harb. Perspect. Biol.1:a003087. doi: 10.1101/cshperspect.a003087
27
BondM. D.Van WartH. E. (1984). Characterization of the individual collagenases from Clostridium histolyticum. Biochemistry23, 3085–3091. doi: 10.1021/bi00308a036
28
BookwalterJ. E.JurcisekJ. A.Gray-OwenS. D.FernandezS.McGillivaryG.BakaletzL. O. (2008). A carcinoembryonic antigen-related cell adhesion molecule 1 homologue plays a pivotal role in nontypeable Haemophilus influenzae colonization of the chinchilla nasopharynx via the outer membrane protein P5-homologous adhesin. Infect. Immun.76, 48–55. doi: 10.1128/IAI.00980-07
29
BrozP.MonackD. M. (2013). Newly described pattern recognition receptors team up against intracellular pathogens. Nat. Rev. Immunol.13, 551–565. doi: 10.1038/nri3479
30
CadiganK. M.WatermanM. L. (2012). TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb. Perspect. Biol.4:a007906. doi: 10.1101/cshperspect.a007906
31
CanoA.Pérez-MorenoM. A.RodrigoI.LocascioA.BlancoM. J.del BarrioM. G.et al. (2000). The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol.2, 76–83. doi: 10.1038/35000025
32
CarterA. T.PeckM. W. (2015). Genomes, neurotoxins and biology of Clostridium botulinum group I and group II. Res. Microbiol.166, 303–317. doi: 10.1016/j.resmic.2014.10.010
33
CashH. L.WhithamC. V.BehrendtC. L.HooperL. V. (2006). Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science313, 1126–1130. doi: 10.1126/science.1127119
34
CepekK. L.ParkerC. M.MadaraJ. L.BrennerM. B. (1993). Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cells. J. Immunol.150, 3459–3470.
35
CepekK. L.ShawS. K.ParkerC. M.RussellG. J.MorrowJ. S.RimmD. L.et al. (1994). Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature372, 190–193. doi: 10.1038/372190a0
36
Cerf-BensussanN.JarryA.BrousseN.Lisowska-GrospierreB.Guy-GrandD.GriscelliC. (1987). A monoclonal antibody (HML-1) defining a novel membrane molecule present on human intestinal lymphocytes. Eur. J. Immunol.17, 1279–1285. doi: 10.1002/eji.1830170910
37
ChambersF. G.KoshyS. S.SaidiR. F.ClarkD. P.MooreR. D.SearsC. L. (1997). Bacteroides fragilis toxin exhibits polar activity on monolayers of human intestinal epithelial cells (T84 cells) in vitro. Infect. Immun.65, 3561–3570. PMID:
38
ChungL.OrbergE. T.GeisA. L.ChanJ. L.FuK.DeStefano ShieldsC. E.et al. (2018). Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe23, 203–214.e5. doi: 10.1016/j.chom.2018.01.007
39
ColpittsC. C.LupbergerJ.BaumertT. F. (2016). Multifaceted role of E-cadherin in hepatitis C virus infection and pathogenesis. Proc. Natl. Acad. Sci. USA113, 7298–7300. doi: 10.1073/pnas.1607732113
40
CossartP.SansonettiP. J. (2004). Bacterial invasion: the paradigms of enteroinvasive pathogens. Science304, 242–248. doi: 10.1126/science.1090124
41
CronanM. R.BeermanR. W.RosenbergA. F.SaelensJ. W.JohnsonM. G.OehlersS. H.et al. (2016). Macrophage epithelial reprogramming underlies mycobacterial granuloma formation and promotes infection. Immunity45, 861–876. doi: 10.1016/j.immuni.2016.09.014
42
DavidsonB.BernerA.NeslandJ. M.RisbergB.BernerH. S.TropèC. G.et al. (2000). E-cadherin and alpha-, beta-, and gamma-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J. Pathol.192, 460–469. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH726>3.0.CO;2-M
43
de la RocheM.WormJ.BienzM. (2008). The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells. BMC Cancer8:199. doi: 10.1186/1471-2407-8-199
44
DesaiM. S.SeekatzA. M.KoropatkinN. M.KamadaN.HickeyC. A.WolterM.et al. (2016). A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell167, 1339–1353.e21. doi: 10.1016/j.cell.2016.10.043
45
DevauxC. A.RaoultD. (2018). The microbiological memory, an epigenetic regulator governing the balance between good health and metabolic disorders. Front. Microbiol.9:1379. doi: 10.3389/fmicb.2018.01379
46
DomannE.WehlandJ.RohdeM.PistorS.HartlM.GoebelW.et al. (1992). A novel bacterial virulence gene in Listeria monocytogenes required for host cell microfilament interaction with homology to the proline-rich region of vinculin. EMBO J.11, 1981–1990. doi: 10.1002/j.1460-2075.1992.tb05252.x
47
DoulgereJ.OttoB.NassourM.Wolters-EisfeldG.RohdeH.MagnusT.et al. (2015). Soluble plasma VE-cadherin concentrations are elevated in patients with STEC infection and haemolytic uraemic syndrome: a case-control study. BMJ Open5:e005659. doi: 10.1136/bmjopen-2014-005659
48
DumlerJ. S.SinclairS. H.ShettyA. C. (2018). Alternative splicing of differentiated myeloid cell transcripts after infection by Anaplasma phagocytophilum impacts a selective group of cellular programs. Front. Cell. Infect. Microbiol.8:14. doi: 10.3389/fcimb.2018.00014. eCollection 2018.
49
EgusaH.NikawaH.MakihiraS.JewettA.YataniH.HamadaT. (2005). Intercellular adhesion molecule 1-dependent activation of interleukin 8 expression in Candida albicans-infected human gingival epithelial cells. Infect. Immun.73, 622–626. doi: 10.1128/IAI.73.1.622-626.2005
50
ElloulS.SilinsI.TropéC. G.BenshushanA.DavidsonB.ReichR. (2006). Expression of E-cadherin transcriptional regulators in ovarian carcinoma. Virchows Arch.449, 520–528. doi: 10.1007/s00428-006-0274-6
51
ElmiA.NasherF.JagatiaH.GundogduO.Bajaj-ElliottM.WrenB.et al. (2016). Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin. Cell. Microbiol.18, 561–572. doi: 10.1111/cmi.12534
52
EschT. R.JonssonM. V.LevanosV. A.PoveromoJ. D.SorkinB. C. (2000). Leukocytes infiltrating the submandibular glands of NOD mice express E-cadherin. J. Autoimmun.15, 387–393. doi: 10.1006/jaut.2000.0451
53
EshghiA.GaultneyR. A.EnglandP.BrûléS.MirasI.SatoH.et al. (2019). An extracellular Leptospira interrogans leucine-rich repeat protein binds human E- and VE-cadherins. Cell. Microbiol.21:e12949. doi: 10.1111/cmi.12949
54
EvangelistaK.FrancoR.SchwabA.CoburnJ. (2014). Leptospira interrogans binds to cadherins. PLoS Negl. Trop. Dis.8:e2672. doi: 10.1371/journal.pntd.0002672
55
FagottoF. (2013). Looking beyond the Wnt pathway for the deep nature of β-catenin. EMBO Rep.14, 422–433. doi: 10.1038/embor.2013.45
56
FangD.HawkeD.ZhengY.XiaY.MeisenhelderJ.NikaH.et al. (2007). Phosphorylation of beta-catenin by AKT promotes beta-catenin transcriptional activity. J. Biol. Chem.282, 11221–11229. doi: 10.1074/jbc.M611871200
57
GadducciA.FerdeghiniM.CosioS.AnnicchiaricoC.CiampiB.BianchiR.et al. (1999). Preoperative serum E-cadherin assay in patients with ovarian carcinoma. Anticancer Res.19, 769–772. PMID:
58
GallT. M. H.FramptonA. E. (2013). Gene of the month: E-cadherin (CDH1). J. Clin. Pathol.66, 928–932. doi: 10.1136/jclinpath-2013-201768
59
GallinW. J.EdelmanG. M.CunninghamB. A. (1983). Characterization of L-CAM, a major cell adhesion molecule from embryonic liver cells. Proc. Natl. Acad. Sci. USA80, 1038–1042.
60
GarzieraM.CanzonieriV.CannizzaroR.GeremiaS.CaggiariL.De ZorziM.et al. (2013). Identification and characterization of CDH1 germline variants in sporadic gastric cancer patients and in individuals at risk of gastric cancer. PLoS One8:e77035. doi: 10.1371/journal.pone.0077035
61
GiebelerN.ZigrinoP. (2016). A Disintegrin and Metalloprotease (ADAM): historical overview of their functions. Toxins8:122. doi: 10.3390/toxins8040122
62
GoderskaK.Agudo PenaS.AlarconT. (2018). Helicobacter pylori treatment: antibiotics or probiotics. Appl. Microbiol. Biotechnol.102, 1–7. doi: 10.1007/s00253-017-8535-7
63
GodtD.TepassU. (1998). Drosophila oocyte localization is mediated by differential cadherin-based adhesion. Nature395, 387–391. doi: 10.1038/26493
64
GottardiC. J.WongE.GumbinerB. M. (2001). E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J. Cell Biol.153, 1049–1060. doi: 10.1083/jcb.153.5.1049
65
GrabowskaM. M.DayM. L. (2012). Soluble E-cadherin: more than a symptom of disease. Front. Biosci.17, 1948–1964. doi: 10.2741/4031
66
GregoryP. A.BertA. G.PatersonE. L.BarryS. C.TsykinA.FarshidG.et al. (2008). The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol.10, 593–601. doi: 10.1038/ncb1722
67
GriffithsN. J.BradleyC. J.HeydermanR. S.VirjiM. (2007). IFN-gamma amplifies NFkappaB-dependent Neisseria meningitidis invasion of epithelial cells via specific upregulation of CEA-related cell adhesion molecule 1. Cell. Microbiol.9, 2968–2983. doi: 10.1111/j.1462-5822.2007.01038.x
68
GumbinerB. M. (1995). Signal transduction of beta-catenin. Curr. Opin. Cell Biol.7, 634–640. doi: 10.1016/0955-0674(95)80104-9
69
GuoZ.NeilsonL. J.ZhongH.MurrayP. S.ZanivanS.Zaidel-BarR. (2014). E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Sci. Signal.7:rs7. doi: 10.1126/scisignal.2005473
70
GuptaP. K.TripathiD.KulkarniS.RajanM. G. (2016). Mycobacterium tuberculosis H37Rv infected THP-1 cells induce epithelial mesenchymal transition in lung adenocarcinoma epithelial cell line (A549). Cell. Immunol.300, 33–40. doi: 10.1016/j.cellimm.2015.11.007
71
HaH.-L.KwonT.BakI. S.EriksonR. L.KimB. Y.YuD.-Y. (2016). IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice. Oncotarget7, 56944–56957. doi: 10.18632/oncotarget.10922
72
HadleyG. A.BartlettS. T.ViaC. S.RostapshovaE. A.MoainieS. (1997). The epithelial cell-specific integrin, CD103 (alpha E integrin), defines a novel subset of alloreactive CD8+ CTL. J. Immunol.159, 3748–3756.
73
HäseC. C.FinkelsteinR. A. (1993). Bacterial extracellular zinc-containing metalloproteases. Microbiol. Rev.57, 823–837. PMID:
74
HechtA.VleminckxK.StemmlerM. P., van RoyF.KemlerR. (2000). The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J.19, 1839–1850. doi: 10.1093/emboj/19.8.1839
75
HermistonM. L.WongM. H.GordonJ. I. (1996). Forced expression of E-cadherin in the mouse intestinal epithelium slows cell migration and provides evidence for nonautonomous regulation of cell fate in a self-renewing system. Genes Dev.10, 985–996. doi: 10.1101/gad.10.8.985
76
HertleR.SchwarzH. (2004). Serratia marcescens internalization and replication in human bladder epithelial cells. BMC Infect. Dis.4:16. doi: 10.1186/1471-2334-4-16
77
HofmannM.PircherH. (2011). E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands. Proc. Natl. Acad. Sci. USA108, 16741–16746. doi: 10.1073/pnas.1107200108
78
HoyB.GeppertT.BoehmM.ReisenF.PlattnerP.GadermaierG.et al. (2012). Distinct roles of secreted HtrA proteases from gram-negative pathogens in cleaving the junctional protein and tumor suppressor E-cadherin. J. Biol. Chem.287, 10115–10120. doi: 10.1074/jbc.C111.333419
79
HoyB.LöwerM.WeydigC.CarraG.TegtmeyerN.GeppertT.et al. (2010). Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep.11, 798–804. doi: 10.1038/embor.2010.114
80
HuberO.KornR.McLaughlinJ.OhsugiM.HerrmannB. G.KemlerR. (1996). Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech. Dev.59, 3–10. doi: 10.1016/0925-4773(96)00597-7
81
HulpiauP.van RoyF. (2009). Molecular evolution of the cadherin superfamily. Int. J. Biochem. Cell Biol.41, 349–369. doi: 10.1016/j.biocel.2008.09.027
82
HyafilF.BabinetC.JacobF. (1981). Cell-cell interactions in early embryogenesis: a molecular approach to the role of calcium. Cell26, 447–454. doi: 10.1016/0092-8674(81)90214-2
83
InoshimaI.InoshimaN.WilkeG. A.PowersM. E.FrankK. M.WangY.et al. (2011). A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat. Med.17, 1310–1314. doi: 10.1038/nm.2451
84
IsbergR. R.LeongJ. M. (1990). Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells. Cell60, 861–871. doi: 10.1016/0092-8674(90)90099-Z
85
IsmailA. S.BehrendtC. L.HooperL. V. (2009). Reciprocal interactions between commensal bacteria and gamma delta intraepithelial lymphocytes during mucosal injury. J. Immunol.182, 3047–3054. doi: 10.4049/jimmunol.0802705
86
IsmailA. S.SeversonK. M.VaishnavaS.BehrendtC. L.YuX.BenjaminJ. L.et al. (2011). Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc. Natl. Acad. Sci. USA108, 8743–8748. doi: 10.1073/pnas.1019574108
87
ItoM.MaruyamaT.SaitoN.KoganeiS.YamamotoK.MatsumotoN. (2006). Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J. Exp. Med.203, 289–295. doi: 10.1084/jem.20051986
88
JavaheriA.KruseT.MoonensK.Mejías-LuqueR.DebraekeleerA.AscheC. I.et al. (2016). Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs. Nat. Microbiol.2:16189. doi: 10.1038/nmicrobiol.2016.243
89
JeanesA.GottardiC. J.YapA. S. (2008). Cadherins and cancer: how does cadherin dysfunction promote tumor progression?Oncogene27, 6920–6929. doi: 10.1038/onc.2008.343
90
JiangH.GuanG.ZhangR.LiuG.ChengJ.HouX.et al. (2009). Identification of urinary soluble E-cadherin as a novel biomarker for diabetic nephropathy. Diabetes Metab. Res. Rev.25, 232–241. doi: 10.1002/dmrr.940
91
JohnsonS. K.RamaniV. C.HenningsL.HaunR. S. (2007). Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin. Cancer109, 1811–1820. doi: 10.1002/cncr.22606
92
JordansS.Jenko-KokaljS.KühlN. M.TedelindS.SendtW.BrömmeD.et al. (2009). Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions. BMC Biochem.10:23. doi: 10.1186/1471-2091-10-23
93
KagueE.ThomaziniC. M.PardiniM. I. de C. M.CarvalhoF.deLeiteC. V.PinheiroN. A. (2010). Methylation status of CDH1 gene in samples of gastric mucous from Brazilian patients with chronic gastritis infected by Helicobacter pylori. Arq. Gastroenterol.47, 7–12. doi: 10.1590/S0004-28032010000100002
94
KalamH.SinghK.ChauhanK.FontanaM. F.KumarD. (2018). Alternate splicing of transcripts upon Mycobacterium tuberculosis infection impacts the expression of functional protein domains. IUBMB Life70, 845–854. doi: 10.1002/iub.1887
95
KatohM. (2017). Canonical and non-canonical WNT signaling in cancer stem cells and their niches: cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (review). Int. J. Oncol.51, 1357–1369. doi: 10.3892/ijo.2017.4129
96
KatzJ. (2002). Hydrolysis of epithelial junctional proteins by porphyromonas gingivalis gingipains. Infect. Immun.70, 2512–2518. doi: 10.1128/IAI.70.5.2512-2518.2002
97
KatzJ.SambandamV.WuJ. H.MichalekS. M.BalkovetzD. F. (2000). Characterization of porphyromonas gingivalis-induced degradation of epithelial cell junctional complexes. Infect. Immun.68, 1441–1449. doi: 10.1128/IAI.68.3.1441-1449.2000
98
KemlerR. (1993). From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion. Trends Genet.9, 317–321.
99
KilshawP. J. (1999). Alpha E beta 7. Mol. Pathol.52, 203–207. doi: 10.1136/mp.52.4.203
100
KilshawP. J.MurantS. J. (1990). A new surface antigen on intraepithelial lymphocytes in the intestine. Eur. J. Immunol.20, 2201–2207. doi: 10.1002/eji.1830201008
101
KimM.AshidaH.OgawaM.YoshikawaY.MimuroH.SasakawaC. (2010). Bacterial interactions with the host epithelium. Cell Host Microbe8, 20–35. doi: 10.1016/j.chom.2010.06.006
102
KimY. S.HoS. B. (2010). Intestinal goblet cells and mucins in health and disease: recent insights and progress. Curr. Gastroenterol. Rep.12, 319–330. doi: 10.1007/s11894-010-0131-2
103
KimC.KimD. G.ParkS. H.HwangY. I.JangS. H.KimC. H.et al. (2011). Epithelial to mesenchymal transition of mesothelial cells in tuberculous pleurisy. Yonsei Med. J.52, 51–58. doi: 10.3349/ymj.2011.52.1.51
104
KleinT.BischoffR. (2011). Physiology and pathophysiology of matrix metalloproteases. Amino Acids41, 271–290. doi: 10.1007/s00726-010-0689-x
105
KluckyB.MuellerR.VogtI.TeurichS.HartensteinB.BreuhahnK.et al. (2007). Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion. Cancer Res.67, 8198–8206. doi: 10.1158/0008-5472.CAN-07-0607
106
KourtidisA.NgokS. P.AnastasiadisP. Z. (2013). p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog. Mol. Biol. Transl. Sci.116, 409–432. doi: 10.1016/B978-0-12-394311-8.00018-2
107
KrampsT.PeterO.BrunnerE.NellenD.FroeschB.ChatterjeeS.et al. (2002). Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell109, 47–60. doi: 10.1016/S0092-8674(02)00679-7
108
KueferR.HoferM. D.ZornC. S. M.EngelO.VolkmerB. G.Juarez-BritoM. A.et al. (2005). Assessment of a fragment of e-cadherin as a serum biomarker with predictive value for prostate cancer. Br. J. Cancer92, 2018–2023. doi: 10.1038/sj.bjc.6602599
109
KumarR.HeroldJ. L.SchadyD.DavisJ.KopetzS.Martinez-MoczygembaM.et al. (2017). Streptococcus gallolyticus sub sp. gallolyticus promotes colorectal tumor development. PLoS Pathog.13:e1006440. doi: 10.1371/journal.ppat.1006440
110
LaursonJ.KhanS.ChungR.CrossK.RajK. (2010). Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. Carcinogenesis31, 918–926. doi: 10.1093/carcin/bgq027
111
LeeK. H.ChoiE. Y.HyunM. S.JangB. I.KimT. N.KimS. W.et al. (2007). Association of extracellular cleavage of E-cadherin mediated by MMP-7 with HGF-induced in vitro invasion in human stomach cancer cells. Eur. Surg. Res.39, 208–215. doi: 10.1159/000101452
112
LeeH.-J.LeeH.-J.LimE.-S.AhnK.-S.ShimB.-S.KimH.-M.et al. (2005). Cambodian Phellinus linteus inhibits experimental metastasis of melanoma cells in mice via regulation of urokinase type plasminogen activator. Biol. Pharm. Bull.28, 27–31. doi: 10.1248/bpb.28.27
113
LeeK. H.ShinS. J.KimK. O.KimM. K.HyunM. S.KimT. N.et al. (2006). Relationship between E-cadherin, matrix metalloproteinase-7 gene expression and clinicopathological features in gastric carcinoma. Oncol. Rep.16, 823–830. doi: 10.3892/or.16.4.823
114
LeeM. G.TangA.SharrowS. O.UdeyM. C. (1994). Murine dendritic epidermal T cells express the homophilic adhesion molecule E-cadherin. Epithelial Cell Biol.3, 149–155. PMID:
115
LiX.-W.ShiB.-Y.YangQ.-L.WuJ.WuH.-M.WangY.-F.et al. (2015). Epigenetic regulation of CDH1 exon 8 alternative splicing in gastric cancer. BMC Cancer15:954. doi: 10.1186/s12885-015-1983-5
116
LiQ.SodroskiC.LoweyB.SchweitzerC. J.ChaH.ZhangF.et al. (2016). Hepatitis C virus depends on E-cadherin as an entry factor and regulates its expression in epithelial-to-mesenchymal transition. Proc. Natl. Acad. Sci. USA113, 7620–7625. doi: 10.1073/pnas.1602701113
117
LiL.WangS.JezierskiA.Moalim-NourL.MohibK.ParksR. J.et al. (2010). A unique interplay between Rap1 and E-cadherin in the endocytic pathway regulates self-renewal of human embryonic stem cells. Stem Cells28, 247–257. doi: 10.1002/stem.289
118
LombaertsM.van WezelT.PhilippoK.DierssenJ. W. F.ZimmermanR. M. E.OostingJ.et al. (2006). E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br. J. Cancer94, 661–671. doi: 10.1038/sj.bjc.6602996
119
MaC.LuoH.GaoF.TangQ.ChenW. (2018). Fusobacterium nucleatum promotes the progression of colorectal cancer by interacting with E-cadherin. Oncol. Lett.16, 2606–2612. doi: 10.3892/ol.2018.8947
120
MacDonaldB. T.TamaiK.HeX. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell17, 9–26. doi: 10.1016/j.devcel.2009.06.016
121
MadouxF.DreymullerD.PettiloudJ.-P.SantosR.Becker-PaulyC.LudwigA.et al. (2016). Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate. Sci. Rep.6:11. doi: 10.1038/s41598-016-0013-4
122
MarambaudP. (2002). A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J.21, 1948–1956. doi: 10.1093/emboj/21.8.1948
123
MaretzkyT.ScholzF.KötenB.ProkschE.SaftigP.ReissK. (2008). ADAM10-mediated E-cadherin release is regulated by proinflammatory cytokines and modulates keratinocyte cohesion in eczematous dermatitis. J. Invest. Dermatol.128, 1737–1746. doi: 10.1038/sj.jid.5701242
124
MarshallD. C.LymanS. K.McCauleyS.KovalenkoM.SpanglerR.LiuC.et al. (2015). Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer. PLoS One10:e0127063. doi: 10.1371/journal.pone.0127063
125
MasonK. L.HuffnagleG. B. (2009). Control of mucosal polymicrobial populations by innate immunity. Cell. Microbiol.11, 1297–1305. doi: 10.1111/j.1462-5822.2009.01347.x
126
MatosM. L.LapyckyjL.RossoM.BessoM. J.MencucciM. V.BriggilerC. I.et al. (2017). Identification of a novel human E-cadherin splice variant and assessment of its effects upon EMT-related events. J. Cell. Physiol.232, 1368–1386. doi: 10.1002/jcp.25622
127
McCreaP. D.GumbinerB. M. (1991). Purification of a 92-kDa cytoplasmic protein tightly associated with the cell-cell adhesion molecule E-cadherin (uvomorulin). Characterization and extractability of the protein complex from the cell cytostructure. J. Biol. Chem.266, 4514–4520. PMID:
128
McCreaP. D.MaherM. T.GottardiC. J. (2015). Nuclear signaling from cadherin adhesion complexes. Curr. Top. Dev. Biol.129–196. doi: 10.1016/bs.ctdb.2014.11.018
129
MelenotteC.MezouarS.Ben AmaraA.BenattiS.ChiaroniJ.DevauxC.et al. (2019). A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever. PLoS One14:e0217542. doi: 10.1371/journal.pone.0217542
130
MelenotteC.MillionM.AudolyG.GorseA.DutroncH.RolandG.et al. (2016). B-cell non-Hodgkin lymphoma linked to Coxiella burnetii. Blood127, 113–121. doi: 10.1182/blood-2015-04-639617
131
MezouarS.Omar OsmanI.MelenotteC.SlimaniC.ChartierC.RaoultD.et al. (2019). High concentrations of serum soluble E-cadherin in patients with Q fever. Front. Cell. Infect. Microbiol.9:219. doi: 10.3389/fcimb.2019.00219
132
MillerH.ZhangJ.KuoleeR.PatelG. B.ChenW. (2007). Intestinal M cells: the fallible sentinels?World J. Gastroenterol.13, 1477–1486. doi: 10.3748/wjg.v13.i10.1477
133
MoonD. C.ChoiC. H.LeeS. M.LeeJ. H.KimS. I.KimD. S.et al. (2012). Nuclear translocation of Acinetobacter baumannii transposase induces DNA methylation of CpG regions in the promoters of E-cadherin gene. PLoS One7:e38974. doi: 10.1371/journal.pone.0038974
134
MüllerK. M.LuedeckerC. J.UdeyM. C.FarrA. G. (1997). Involvement of E-cadherin in thymus organogenesis and thymocyte maturation. Immunity6, 257–264. doi: 10.1016/S1074-7613(00)80328-3
135
MunroS. B.DuclosA. J.JacksonA. R.BainesM. G.BlaschukO. W. (1996). Characterization of cadherins expressed by murine thymocytes. Cell. Immunol.169, 309–312. doi: 10.1006/cimm.1996.0123
136
Murata-KamiyaN.KurashimaY.TeishikataY.YamahashiY.SaitoY.HigashiH.et al. (2007). Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene26, 4617–4626. doi: 10.1038/sj.onc.1210251
137
NagafuchiA.TakeichiM. (1988). Cell binding function of E-cadherin is regulated by the cytoplasmic domain. EMBO J.7, 3679–3684. doi: 10.1002/j.1460-2075.1988.tb03249.x
138
NagaseH.VisseR.MurphyG. (2006). Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res.69, 562–573. doi: 10.1016/j.cardiores.2005.12.002
139
NajyA. J.DayK. C.DayM. L. (2008). The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation. J. Biol. Chem.283, 18393–18401. doi: 10.1074/jbc.M801329200
140
NavaP.KamekuraR.NusratA. (2013). Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis. Tissue Barriers1:e24783. doi: 10.4161/tisb.24783
141
NiessenC. M.LeckbandD.YapA. S. (2011). Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol. Rev.91, 691–731. doi: 10.1152/physrev.00004.2010
142
NoëV.FingletonB.JacobsK.CrawfordH. C.VermeulenS.SteelantW.et al. (2001). Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J. Cell Sci.114, 111–118. PMID:
143
NolletF.KoolsP.van RoyF. (2000). Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J. Mol. Biol.299, 551–572. doi: 10.1006/jmbi.2000.3777
144
NovotnyL. A.BakaletzL. O. (2016). Intercellular adhesion molecule 1 serves as a primary cognate receptor for the type IV pilus of nontypeable Haemophilus influenzae: ICAM1 serves as the cognate receptor for NTHI type IV pilus. Cell. Microbiol.18, 1043–1055. doi: 10.1111/cmi.12575
145
NusratA.von Eichel-StreiberC.TurnerJ. R.VerkadeP.MadaraJ. L.ParkosC. A. (2001). Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect. Immun.69, 1329–1336. doi: 10.1128/IAI.69.3.1329-1336.2001
146
O’ConnorP. M.LapointeT. K.JacksonS.BeckP. L.JonesN. L.BuretA. G. (2011). Helicobacter pylori activates calpain via toll-like receptor 2 to disrupt adherens junctions in human gastric epithelial cells. Infect. Immun.79, 3887–3894. doi: 10.1128/IAI.05109-11
147
ObisoR. J.AzghaniA. O.WilkinsT. D. (1997). The Bacteroides fragilis toxin fragilysin disrupts the paracellular barrier of epithelial cells. Infect. Immun.65, 1431–1439. PMID:
148
OdaH.TakeichiM. (2011). Structural and functional diversity of cadherin at the adherens junction. J. Cell Biol.193, 1137–1146. doi: 10.1083/jcb.201008173
149
OgataY.EnghildJ. J.NagaseH. (1992). Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J. Biol. Chem.267, 3581–3584. PMID:
150
OgouS. I.Yoshida-NoroC.TakeichiM. (1983). Calcium-dependent cell-cell adhesion molecules common to hepatocytes and teratocarcinoma stem cells. J. Cell Biol.97, 944–948. doi: 10.1083/jcb.97.3.944
151
OhiraT.GemmillR. M.FergusonK.KusyS.RocheJ.BrambillaE.et al. (2003). WNT7a induces E-cadherin in lung cancer cells. Proc. Natl. Acad. Sci. USA100, 10429–10434. doi: 10.1073/pnas.1734137100
152
OkadaY.NakanishiI. (1989). Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G. FEBS Lett.249, 353–356. doi: 10.1016/0014-5793(89)80657-X
153
OrtegaF. E.RengarajanM.ChavezN.RadhakrishnanP.GloerichM.BianchiniJ.et al. (2017). Adhesion to the host cell surface is sufficient to mediate Listeria monocytogenes entry into epithelial cells. Mol. Biol. Cell28, 2945–2957. doi: 10.1091/mbc.E16-12-0851
154
PandiellaA.BosenbergM. W.HuangE. J.BesmerP.MassaguéJ. (1992). Cleavage of membrane-anchored growth factors involves distinct protease activities regulated through common mechanisms. J. Biol. Chem.267, 24028–24033. PMID:
155
PerriF.CotugnoR.PiepoliA.MerlaA.QuitadamoM.GentileA.et al. (2007). Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. Am. J. Gastroenterol.102, 1361–1371. doi: 10.1111/j.1572-0241.2007.01284.x
156
PhanQ. T.MyersC. L.FuY.SheppardD. C.YeamanM. R.WelchW. H.et al. (2007). Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol.5:e64. doi: 10.1371/journal.pbio.0050064
157
PietersT.van RoyF. (2014). Role of cell-cell adhesion complexes in embryonic stem cell biology. J. Cell Sci.127, 2603–2613. doi: 10.1242/jcs.146720
158
PittardA. J.BanksR. E.GalleyH. F.WebsterN. R. (1996). Soluble E-cadherin concentrations in patients with systemic inflammatory response syndrome and multiorgan dysfunction syndrome. Br. J. Anaesth.76, 629–631. doi: 10.1093/bja/76.5.629
159
RajićJ.Inic-KanadaA.SteinE.DinićS.SchuererN.UskokovićA.et al. (2017). Chlamydia trachomatis infection is associated with E-cadherin promoter methylation, downregulation of E-cadherin expression, and increased expression of fibronectin and α-SMA—implications for epithelial-mesenchymal transition. Front. Cell. Infect. Microbiol.7:253. doi: 10.3389/fcimb.2017.00253
160
ReboudE.BassoP.MaillardA. P.HuberP.AttréeI. (2017). Exolysin shapes the virulence of Pseudomonas aeruginosa clonal outliers. Toxins9, pii: E364. doi: 10.3390/toxins9110364
161
RemacleA. G.ShiryaevS. A.StronginA. Y. (2014). Distinct interactions with cellular E-cadherin of the two virulent metalloproteinases encoded by a Bacteroides fragilis pathogenicity island. PLoS One9:e113896. doi: 10.1371/journal.pone.0113896
162
RepettoO.De PaoliP.De ReV.CanzonieriV.CannizzaroR. (2014). Levels of soluble E-cadherin in breast, gastric, and colorectal cancers. Biomed. Res. Int.2014:408047. doi: 10.1155/2014/408047
163
ReyatJ. S.ChimenM.NoyP. J.SzyrokaJ.RaingerG. E.TomlinsonM. G. (2017). ADAM10-interacting tetraspanins Tspan5 and Tspan17 regulate VE-cadherin expression and promote T lymphocyte transmigration. J. Immunol.199, 666–676. doi: 10.4049/jimmunol.1600713
164
RodriguezF. J.Lewis-TuffinL. J.AnastasiadisP. Z. (2012). E-cadherin’s dark side: possible role in tumor progression. Biochim. Biophys. Acta1826, 23–31. doi: 10.1016/j.bbcan.2012.03.002
165
RossoM.LapyckyiL.BessoM. L.MongeM.ReventósJ.CanalsF.et al. (2019). Characterization of the molecular changes associated with the overexpression of a novel epithelial cadherin splice variant mRNA in a breast cancer model using proteomics and bioinformatics approaches: identification of changes in cell metabolism and an increased expression of lactate dehydrogenase B. Cancer Metab.7:5. doi: 10.1186/s40170-019-0196-9
166
RouabhiaM.SemlaliA.AudoyJ.ChmielewskiW. (2012). Antagonistic effect of Candida albicans and IFNγ on E-cadherin expression and production by human primary gingival epithelial cells. Cell. Immunol.280, 61–67. doi: 10.1016/j.cellimm.2012.11.008
167
RubinsteinM. R.BaikJ. E.LaganaS. M.HanR. P.RaabW. J.SahooD.et al. (2019). Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β-catenin modulator Annexin A1. EMBO Rep.20, pii: e47638. doi: 10.15252/embr.201847638
168
RubinsteinM. R.WangX.LiuW.HaoY.CaiG.HanY. W. (2013). Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe14, 195–206. doi: 10.1016/j.chom.2013.07.012
169
RyniersF.StoveC.GoethalsM.BrackenierL.NoëV.BrackeM.et al. (2002). Plasmin produces an E-cadherin fragment that stimulates cancer cell invasion. Biol. Chem.383, 159–165. doi: 10.1515/BC.2002.016
170
SakaiA.SugawaraY.KuroishiT.SasanoT.SugawaraS. (2008). Identification of IL-18 and Th17 cells in salivary glands of patients with Sjogren’s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J. Immunol.181, 2898–2906. doi: 10.4049/jimmunol.181.4.2898
171
SalamaR. H. M.SelemT. H.El-GammalM.ElhagagyA. A.BakarS. M. (2013). Urinary tumor markers could predict survival in bladder carcinoma. Indian J. Clin. Biochem.28, 265–271. doi: 10.1007/s12291-012-0266-z
172
SatoT.ShibataW.MaedaS. (2019). Adhesion molecules and pancreatitis. J. Gastroenterol.54, 99–107. doi: 10.1007/s00535-018-1500-0
173
Sauka-SpenglerT.Bronner-FraserM. (2008). A gene regulatory network orchestrates neural crest formation. Nat. Rev. Mol. Cell Biol.9, 557–568. doi: 10.1038/nrm2428
174
SchiavoG.BenfenatiF.PoulainB.RossettoO.Polverino de LauretoP.DasGuptaB. R.et al. (1992). Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature359, 832–835. doi: 10.1038/359832a0
175
SchirrmeisterW.GnadT.WexT.HigashiyamaS.WolkeC.NaumannM.et al. (2009). Ectodomain shedding of E-cadherin and c-met is induced by Helicobacter pylori infection. Exp. Cell Res.315, 3500–3508. doi: 10.1016/j.yexcr.2009.07.029
176
SchmidtT. P.PernaA. M.FugmannT.BöhmM.JanH.HallerS.et al. (2016). Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Sci. Rep.6:23264. doi: 10.1038/srep23264
177
SchuhR.VestweberD.RiedeI.RingwaldM.RosenbergU. B.JäckleH.et al. (1986). Molecular cloning of the mouse cell adhesion molecule uvomorulin: cDNA contains a B1-related sequence. Proc. Natl. Acad. Sci. USA83, 1364–1368.
178
SchwartzkopffS.GründemannC.SchweierO.RosshartS.KarjalainenK. E.BeckerK.-F.et al. (2007). Tumor-associated E-cadherin mutations affect binding to the killer cell lectin-like receptor G1 in humans. J. Immunol.179, 1022–1029. doi: 10.4049/jimmunol.179.2.1022
179
SeikeS.TakeharaM.TakagishiT.MiyamotoK.KobayashiK.NagahamaM. (2018). Delta-toxin from Clostridium perfringens perturbs intestinal epithelial barrier function in Caco-2 cell monolayers. Biochim. Biophys. Acta Biomembr.1860, 428–433. doi: 10.1016/j.bbamem.2017.10.003
180
SeveauS.BierneH.GirouxS.PrévostM.-C.CossartP. (2004). Role of lipid rafts in E-cadherin- and HGF-R/met-mediated entry of Listeria monocytogenes into host cells. J. Cell Biol.166, 743–753. doi: 10.1083/jcb.200406078
181
ShapiroL.FannonA. M.KwongP. D.ThompsonA.LehmannM. S.GrübelG.et al. (1995). Structural basis of cell-cell adhesion by cadherins. Nature374, 327–337. doi: 10.1038/374327a0
182
SharmaS.LichtensteinA. (2009). Aberrant splicing of the E-cadherin transcript is a novel mechanism of gene silencing in chronic lymphocytic leukemia cells. Blood114, 4179–4185. doi: 10.1182/blood-2009-03-206482
183
SheetsS. M.PotempaJ.TravisJ.CasianoC. A.FletcherH. M. (2005). Gingipains from Porphyromonas gingivalis W83 induce cell adhesion molecule cleavage and apoptosis in endothelial cells. Infect. Immun.73, 1543–1552. doi: 10.1128/IAI.73.3.1543-1552.2005
184
SheridanB. S.LefrançoisL. (2011). Regional and mucosal memory T cells. Nat. Immunol.12, 485–491. doi: 10.1038/ni.2029
185
ShieldsB. D.KossB.TaylorE. M.StoreyA. J.WestK. L.ByrumS. D.et al. (2019). Loss of E-cadherin inhibits CD103 antitumor activity and reduces checkpoint blockade responsiveness in melanoma. Cancer Res.79, 1113–1123. doi: 10.1158/0008-5472.CAN-18-1722
186
ShirahataT.NakamuraH.NakajimaT.NakamuraM.ChubachiS.YoshidaS.et al. (2018). Plasma sE-cadherin and the plasma sE-cadherin/sVE-cadherin ratio are potential biomarkers for chronic obstructive pulmonary disease. Biomarkers23, 414–421. doi: 10.1080/1354750X.2018.1434682
187
SintsovaA.WongH.MacDonaldK. S.KaulR.VirjiM.Gray-OwenS. D. (2015). Selection for a CEACAM receptor-specific binding phenotype during Neisseria gonorrhoeae infection of the human genital tract. Infect. Immun.83, 1372–1383. doi: 10.1128/IAI.03123-14
188
StephensG. L.AnderssonJ.ShevachE. M. (2007). Distinct subsets of FoxP3+ regulatory T cells participate in the control of immune responses. J. Immunol.178, 6901–6911. doi: 10.4049/jimmunol.178.11.6901
189
StreeckH.KwonD. S.PyoA.FlandersM.ChevalierM. F.LawK.et al. (2011). Epithelial adhesion molecules can inhibit HIV-1-specific CD8+ T-cell functions. Blood117, 5112–5122. doi: 10.1182/blood-2010-12-321588
190
SugawaraY.FujinagaY. (2011). The botulinum toxin complex meets E-cadherin on the way to its destination. Cell Adhes. Migr.5, 34–36. doi: 10.4161/cam.5.1.13574
191
SunH. (2017). Deciphering alternative splicing and nonsense-mediated decay modulate expression in primary lymphoid tissues of birds infected with avian pathogenic E. coli (APEC). BMC Genet.18:21. doi: 10.1186/s12863-017-0488-4
192
SunH.PanL.JiaH.ZhangZ.GaoM.HuangM.et al. (2018). Label-free quantitative proteomics identifies novel plasma biomarkers for distinguishing pulmonary tuberculosis and latent infection. Front. Microbiol.9:1267. doi: 10.3389/fmicb.2018.01267
193
SuzukiM.MimuroH.SuzukiT.ParkM.YamamotoT.SasakawaC. (2005). Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J. Exp. Med.202, 1235–1247. doi: 10.1084/jem.20051027
194
SymowiczJ.AdleyB. P.GleasonK. J.JohnsonJ. J.GhoshS.FishmanD. A.et al. (2007). Engagement of collagen-binding integrins promotes matrix metalloproteinase-9–dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res.67, 2030–2039. doi: 10.1158/0008-5472.CAN-06-2808
195
TaharaT.YamamotoE.SuzukiH.MaruyamaR.ChungW.GarrigaJ.et al. (2014). Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res.74, 1311–1318. doi: 10.1158/0008-5472.CAN-13-1865
196
TakeichiM. (1977). Functional correlation between cell adhesive properties and some cell surface proteins. J. Cell Biol.75, 464–474. doi: 10.1083/jcb.75.2.464
197
TchoupaA. K.LichteneggerS.ReidlJ.HauckC. R. (2015). Outer membrane protein P1 is the CEACAM-binding adhesin of Haemophilus influenzae: P1 binds human CEACAMs to colonize mucosa. Mol. Microbiol.98, 440–455. doi: 10.1111/mmi.13134
198
TegtmeyerN.HarrerA.SchmittV.SingerB. B.BackertS. (2019). Expression of CEACAM1 or CEACAM5 in AZ-521 cells restores the type IV secretion deficiency for translocation of CagA by Helicobacter pylori. Cell. Microbiol.21:e12965. doi: 10.1111/cmi.12965
199
TegtmeyerN.WesslerS.NecchiV.RohdeM.HarrerA.RauT. T.et al. (2017). Helicobacter pylori employs a unique basolateral type IV secretion mechanism for CagA delivery. Cell Host Microbe22, 552–560.e5. doi: 10.1016/j.chom.2017.09.005
200
TercioloC.DobricA.OuaissiM.SiretC.BreuzardG.SilvyF.et al. (2017). Saccharomyces boulardii CNCM I-745 restores intestinal barrier integrity by regulation of E-cadherin recycling. J. Crohns Colitis11, 999–1010. doi: 10.1093/ecco-jcc/jjx030
201
TessmerM. S.FugereC.StevenaertF.NaidenkoO. V.ChongH. J.LeclercqG.et al. (2007). KLRG1 binds cadherins and preferentially associates with SHIP-1. Int. Immunol.19, 391–400. doi: 10.1093/intimm/dxm004
202
ThieryJ. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer2, 442–454. doi: 10.1038/nrc822
203
ThoulouzeM. I.LafageM.SchachnerM.HartmannU.CremerH.LafonM. (1998). The neural cell adhesion molecule is a receptor for rabies virus. J. Virol.72, 7181–7190. PMID:
204
TsaurI.ThurnK.JuengelE.GustK. M.BorgmannH.MagerR.et al. (2015). sE-cadherin serves as a diagnostic and predictive parameter in prostate cancer patients. J. Exp. Clin. Cancer Res.34:43. doi: 10.1186/s13046-015-0161-6
205
TuccinardiT.NutiE.OrtoreG.RosselloA.AvramovaS. I.MartinelliA. (2008). Development of a receptor-based 3D-QSAR study for the analysis of MMP2, MMP3, and MMP9 inhibitors. Bioorg. Med. Chem.16, 7749–7758. doi: 10.1016/j.bmc.2008.07.004
206
TurkB.TurkD.TurkV. (2012). Protease signalling: the cutting edge. EMBO J.31, 1630–1643. doi: 10.1038/emboj.2012.42
207
UchidaY.KawaiK.IbusukiA.KanekuraT. (2011). Role for E-cadherin as an inhibitory receptor on epidermal T cells. J. Immunol.186, 6945–6954. doi: 10.4049/jimmunol.1003853
208
VallsG.CodinaM.MillerR. K.Del Valle-PérezB.VinyolesM.CaellesC.et al. (2012). Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin. J. Cell Sci.125, 5288–5301. doi: 10.1242/jcs.101030
209
Van den BosscheJ.MalissenB.MantovaniA.De BaetselierP.Van GinderachterJ. A. (2012). Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood119, 1623–1633. doi: 10.1182/blood-2011-10-384289
210
van RoyF. (2014). Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat. Rev. Cancer14, 121–134. doi: 10.1038/nrc3647
211
van RoyF.BerxG. (2008). The cell-cell adhesion molecule E-cadherin. Cell. Mol. Life Sci.65, 3756–3788. doi: 10.1007/s00018-008-8281-1
212
VazeilleE.BringerM.-A.GardarinA.ChambonC.Becker-PaulyC.PenderS. L. F.et al. (2011). Role of meprins to protect ileal mucosa of Crohn’s disease patients from colonization by adherent-invasive E. coli. PLoS One6:e21199. doi: 10.1371/journal.pone.0021199
213
VillarC. C.KashlevaH.NobileC. J.MitchellA. P.Dongari-BagtzoglouA. (2007). Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor Rim101p and protease Sap5p. Infect. Immun.75, 2126–2135. doi: 10.1128/IAI.00054-07
214
WakabayashiT.De StrooperB. (2008). Presenilins: members of the gamma-secretase quartets, but part-time soloists too. Physiology (Bethesda)23, 194–204. doi: 10.1152/physiol.00009.2008
215
WeiW.GuoH.ChangJ.YuY.LiuG.ZhangN.et al. (2016). ICAM-5/Telencephalin is a functional entry receptor for enterovirus D68. Cell Host Microbe20, 631–641. doi: 10.1016/j.chom.2016.09.013
216
WellsA.YatesC.ShepardC. R. (2008). E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin. Exp. Metastasis25, 621–628. doi: 10.1007/s10585-008-9167-1
217
WuG.HuangH.Garcia AbreuJ.HeX. (2009). Inhibition of GSK3 phosphorylation of beta-catenin via phosphorylated PPPSPXS motifs of Wnt coreceptor LRP6. PLoS One4:e4926. doi: 10.1371/journal.pone.0004926
218
WuS.LimK.-C.HuangJ.SaidiR. F.SearsC. L. (1998). Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc. Natl. Acad. Sci. USA95, 14979–14984.
219
WuS.MorinP. J.MaouyoD.SearsC. L. (2003). Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology124, 392–400. doi: 10.1053/gast.2003.50047
220
XuX.ShiY.ZhangP.ZhangF.ShenY.SuX.et al. (2012). E-cadherin mediates adhesion and endocytosis of Aspergillus fumigatus blastospores in human epithelial cells. Chin. Med. J.125, 617–621. doi: 10.3760/cma.j.issn.0366-6999.2012.04.011
221
XuH.SobueT.BertoliniM.ThompsonA.Dongari-BagtzoglouA. (2016). Streptococcus oralis and Candida albicans synergistically activate μ-calpain to degrade E-cadherin from oral epithelial junctions. J. Infect. Dis.214, 925–934. doi: 10.1093/infdis/jiw201
222
YanT.HanJ.YuX. (2015). E-cadherin mediates adhesion of Aspergillus fumigatus to non-small cell lung cancer cells. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med.37, 15593–15599.doi: 10.1007/s13277-015-4195-3
223
YangY.WengW.PengJ.HongL.YangL.ToiyamaY.et al. (2017). Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-κB, and up-regulating expression of MicroRNA-21. Gastroenterology152, 851–866.e24. doi: 10.1053/j.gastro.2016.11.018
224
YapA. S.NiessenC. M.GumbinerB. M. (1998). The juxtamembrane region of the cadherin cytoplasmic tail supports lateral clustering, adhesive strengthening, and interaction with p120ctn. J. Cell Biol.141, 779–789. doi: 10.1083/jcb.141.3.779
225
YoshikawaY.OgawaM.HainT.YoshidaM.FukumatsuM.KimM.et al. (2009). Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat. Cell Biol.11, 1233–1240. doi: 10.1038/ncb1967
226
ZhaoQ.BuschB.Jiménez-SotoL. F.Ishikawa-AnkerholdH.MassbergS.TerradotL.et al. (2018). Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation. PLoS Pathog.14:e1007359. doi: 10.1371/journal.ppat.1007359
227
ZhouZ.ChenJ.YaoH.HuH. (2018). Fusobacterium and colorectal cancer. Front. Oncol.8:371. doi: 10.3389/fonc.2018.00371
Summary
Keywords
bacterial invasion, bacteria-inducing cancer, pathophysiology, E-cadherin, sheddases
Citation
Devaux CA, Mezouar S and Mege J-L (2019) The E-Cadherin Cleavage Associated to Pathogenic Bacteria Infections Can Favor Bacterial Invasion and Transmigration, Dysregulation of the Immune Response and Cancer Induction in Humans. Front. Microbiol. 10:2598. doi: 10.3389/fmicb.2019.02598
Received
19 June 2019
Accepted
25 October 2019
Published
08 November 2019
Volume
10 - 2019
Edited by
Christoph Hölscher, Research Center Borstel (LG), Germany
Reviewed by
Manja Boehm, University of Erlangen Nuremberg, Germany; Mónica Hebe Vazquez-Levin, National Council for Scientific and Technical Research (CONICET), Argentina
Updates
Copyright
© 2019 Devaux, Mezouar and Mege.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Christian A. Devaux, christian.devaux@mediterranee-infection.com
This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.