CAR regulates epithelial cell junction stability through control of E-cadherin trafficking

Morton, Penny E.; Hicks, Allan; Nastos, Theodoros; Santis, George; Parsons, Maddy

doi:10.1038/srep02889

Cited by 32 publications

(58 citation statements)

References 47 publications

(82 reference statements)

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“…Recently, two studies have described a mechanism by which CAR may regulate epithelial intercellular junctions. CAR was found to control E-cadherin stability at cell-cell contacts by promoting the internalization of E-cadherin [64,65]. CAR phosphorylation by PKCδ was shown to regulate Src-dependent endocytosis of E-cadherin at cell junctions.…”

Section: The Role Of Jam Family Members In Mucosal Epithelial Barriermentioning

confidence: 99%

“…Specifically, CAR-dependent E-cadherin endocytosis occurred when CAR is not phosphorylated but PKCδ–dependent phosphorylation resulted in the recovery of E-cadherin at adherens junctions (AJs). These data suggest that PKCδ mediated phosphorylation of CAR maintains E-cadherin at junctions and may serve to stabilize epithelial cell-cell adhesion [65]. Furthermore, the above observations suggest that CAR may act preferentially on the maintenance of epithelial AJs instead of TJs.…”

Section: The Role Of Jam Family Members In Mucosal Epithelial Barriermentioning

confidence: 99%

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JAM-related proteins in mucosal homeostasis and inflammation

2014

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Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include Junctional Adhesion Molecules (JAMs) that belong to the CTX (Cortical Thymocyte marker for Xenopus) family of proteins. JAM family encompasses three classical members (JAM-A, -B and –C) and related molecules including JAM4, JAM-Like protein (JAM-L), Coxsackie and Adenovirus Receptor (CAR), CAR-Like Membrane Protein (CLMP) and Endothelial cell-Selective Adhesion Molecule (ESAM). JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.

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Section: The Role Of Jam Family Members In Mucosal Epithelial Barriermentioning

confidence: 99%

Section: The Role Of Jam Family Members In Mucosal Epithelial Barriermentioning

confidence: 99%

JAM-related proteins in mucosal homeostasis and inflammation

2014

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“…The ICD of CAR contains numerous sequences that could be involved in protein-protein interaction and influence endocytosis (32,33). CAR could also regulate the trafficking of other proteins potentially important for CAV-2 entry, as described for E-cadherin (38) or acid sensing ion channel 3 (39). The ICD of CAR could also influence the ECD of CAR.…”

Section: Discussionmentioning

confidence: 99%

The Intracellular Domain of the Coxsackievirus and Adenovirus Receptor Differentially Influences Adenovirus Entry

Loustalot

Kremer

Salinas

2015

J Virol

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The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule used as a docking molecule by some adenoviruses (AdVs) and group B coxsackieviruses. We previously proposed that the preferential transduction of neurons by canine adenovirus type 2 (CAV-2) is due to CAR-mediated internalization. Our proposed pathway of CAV-2 entry is in contrast to that of human AdV type 5 (HAdV-C5) in nonneuronal cells, where internalization is mediated by auxiliary receptors such as integrins. We therefore asked if in fibroblast-like cells the intracellular domain (ICD) of CAR plays a role in the internalization of the CAV-2 fiber knob (FK CAV ), CAV-2, or HAdV-C5 when the capsid cannot engage integrins. Here, we show that in fibroblast-like cells, the CAR ICD is needed for FK CAV entry and efficient CAV-2 transduction but dispensable for HAdV-C5 and an HAdV-C5 capsid lacking the RGD sequence (an integrin-interacting motif) in the penton. Moreover, the deletion of the CAR ICD further impacts CAV-2 intracellular trafficking, highlighting the crucial role of CAR in CAV-2 intracellular dynamics. These data demonstrate that the CAR ICD contains sequences important for the recruitment of the endocytic machinery that differentially influences AdV cell entry. IMPORTANCEUnderstanding how viruses interact with the host cell surface and reach the intracellular space is of crucial importance for applied and fundamental virology. Here, we compare the role of a cell adhesion molecule (CAR) in the internalization of adenoviruses that naturally infect humans and Canidae. We show that the intracellular domain of CAR differentially regulates AdV entry and trafficking. Our study highlights the mechanistic differences that a receptor can have for two viruses from the same family.A denoviruses (AdVs) infect mammals, reptiles, amphibians, and birds (1). In humans, AdVs cause diseases ranging from mild respiratory and ocular infections to severe or lethal pathologies in immunocompromised hosts (2). There are over 200 AdVs identified, which include more than 56 human AdV (HAdV) types that have been partially characterized. Most of the studies addressing receptor usage and intracellular trafficking have used HAdV type 5 (HAdV-C5) or type 2 (HAdV-C2) and paved the way toward the characterization of how AdVs interact with surface molecules and use the endocytic machinery to access the cytoplasm (2-4).AdVs engage cell surface molecules via their fiber, penton, and hexon proteins (2). The knob region of the fiber (FK) of some of HAdV species A, C, D, E, and F interacts with the coxsackievirus and adenovirus receptor (CAR) (2, 5). CAR is a single-pass transmembrane protein containing an extracellular domain (ECD) composed of two Ig-like domains (D1 and D2), a transmembrane domain (TM), and an intracellular domain (ICD) (6). Several motifs present in the ICD, such as the PDZ domain and the clathrin adaptor protein (AP) binding site, mediate protein-protein interactions (6, 7). Moreover, posttranslational modifications, including glycosyla...

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“…74,93,94 Similar to JAM-A, CAR can engage in homophilic interactions 95 ; however, it also binds JAML, a JAM-like protein expressed exclusively on PMNs, monocytes, and gd T-cells, 74,96 with high affinity. While these observations marked the CAR-JAML ligand pair as an attractive candidate for PMN trafficking regulation, a recent study found that inhibiting these interactions only had a minor effect on PMN TEM.…”

Section: Tight Junction Signaling and Function During Pmn Transepithementioning

confidence: 99%

“…94 Specifically, PKCd-mediated C-terminal CAR phosphorylation stabilizes E-cadherin at the cell junctions, 94 likely resulting in reduced migratory and proliferative phenotypes.…”

Section: Tight Junction Signaling and Function During Pmn Transepithementioning

confidence: 99%

Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

Sumagin¹,

Parkos

2014

Tissue Barriers

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Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function.

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CAR regulates epithelial cell junction stability through control of E-cadherin trafficking

Cited by 32 publications

References 47 publications

JAM-related proteins in mucosal homeostasis and inflammation

JAM-related proteins in mucosal homeostasis and inflammation

The Intracellular Domain of the Coxsackievirus and Adenovirus Receptor Differentially Influences Adenovirus Entry

Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration

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