Interaction of the Coxsackie and adenovirus receptor (CAR) with the cytoskeleton: Binding to actin

Huang, Kuo Cheng; Yasruel, Zivart; Guérin, Claude; Holland, Paul C.; Nalbantoglu, Joséphine

doi:10.1016/j.febslet.2007.05.019

Cited by 32 publications

(28 citation statements)

References 26 publications

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“…Moreover, it has been suggested that CAR may be involved in processes during reorganisation of the cytoskeleton and thereby impact cell migration and invasion. Hereby, binding of CAR to actin, as been shown previously, may pose a central phenomenon (Huang et al, 2007). However, a more detailed understanding of mechanisms underlying functions of CAR in cancer cell motility in general, and gastric cancer cell migration and invasion in particular is currently still missing.…”

Section: Discussionmentioning

confidence: 99%

Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

et al. 2009

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Loss of the coxsackie and adenovirus receptor (CAR) has previously been observed in gastric cancer. The role of CAR in gastric cancer pathobiology, however, is unclear. We therefore analysed CAR in 196 R 0 -resected gastric adenocarcinomas and noncancerous gastric mucosa samples using immunohistochemistry and immunofluorescence. Coxsackie and adenovirus receptor was found at the surface and foveolar epithelium of all non-neoplastic gastric mucosa samples (n ¼ 175), whereas only 56% of gastric cancer specimens showed CAR positivity (Po0.0001). Loss of CAR correlated significantly with decreased differentiation, increased infiltrative depths, presence of distant metastases, and was also associated with reduced carcinoma-specific survival. To clarify whether CAR impacts the tumorbiologic properties of gastric cancer, we subsequently determined the role of CAR in proliferation, migration, and invasion of gastric cancer cell lines by application of specific CAR siRNA or ectopic expression of a human full-length CAR cDNA. These experiments showed that RNAi-mediated CAR knock down resulted in increased proliferation, migration, and invasion of gastric cancer cell lines, whereas enforced ectopic CAR expression led to opposite effects. We conclude that the association of reduced presence of CAR in more severe disease states, together with our findings in gastric cancer cell lines, suggests that CAR functionally contributes to gastric cancer pathogenesis, showing features of a tumour suppressor.

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Section: Discussionmentioning

confidence: 99%

Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

et al. 2009

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“…How CAR is linked to the endocytic machinery and whether this plays other biological roles than pathogen binding remain to be characterized. 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).…”

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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“…28,29 CAR also interacts with actin and microtubules, leading to dynamic reorganization of the cytoskeleton. 13,14 Together, CAR might benefit the bladder uroepithelium under fluid shearing stress by participating in the anchoring junctions between the epithelial cells and basal lamina and by interaction with the cytoskeletons. The lack of an intracellular tail will result in the loss of targeting of CAR to the TJs, and differences in the tail ends between the 2 CAR isoforms (amino acid 340-365 in CAR-1; amino acid 340-352 in CAR-2) affects their subcellular localization.…”

Section: Commentmentioning

confidence: 99%

“…Furthermore, CAR interacts with actin and microtubules, leading to dynamic reorganization of the cytoskeleton. 13,14 The mouse CAR gene is composed of Ն8 exons, and CAR splice variants that differ at the end of the cytoplasmic tail have been identified in a number of tissues. 14,15 CAR can elicit a negative signal cascade to modulate the cell cycle regulators of bladder cancer cells.…”

mentioning

confidence: 99%

“…13,14 The mouse CAR gene is composed of Ն8 exons, and CAR splice variants that differ at the end of the cytoplasmic tail have been identified in a number of tissues. 14,15 CAR can elicit a negative signal cascade to modulate the cell cycle regulators of bladder cancer cells. [16][17][18][19] The loss of CAR decreases cell adhesion, increases migratory potential, and correlates with the invasive phenotype of bladder cancer.…”

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confidence: 99%

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Expression of Coxsackievirus and Adenovirus Receptor Isoforms in Developing Mouse Bladder Uroepithelium

Gye

Lee

et al. 2011

Urology

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Interaction of the Coxsackie and adenovirus receptor (CAR) with the cytoskeleton: Binding to actin

Cited by 32 publications

References 26 publications

Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression

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

Expression of Coxsackievirus and Adenovirus Receptor Isoforms in Developing Mouse Bladder Uroepithelium

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