A role for the PDZ-binding domain of the coxsackie B virus and adenovirus receptor (CAR) in cell adhesion and growth

Abstract

The coxsackie and adenovirus receptor (CAR) plays a role in viral infection, maintenance of the junction adhesion complex in polarized epithelia, and modulation of cellular growth properties. As a viral receptor, the C-terminus appears to play no role indicating that the major function of CAR is to tether the virus to the cell. By contrast, the C-terminus is known to play a role in cellular localization and probably has a significant function in CAR-mediated adhesion and cell growth properties. We hypothesized that the CAR PDZ (PSD-95/Disc-large/ZO-1) binding motif interacts with PDZ-domain-containing proteins to modulate the cellular phenotype. CAR was modified by deleting the last four amino acids (CARΔGSIV) and evaluated for cell-cell adhesion in polarized primary human airway epithelia and growth characteristics in stably transfected L-cells. Although ablation of the CAR PDZ-binding motif did not affect adenoviral infection, it did have a significant effect both on cell-cell adhesion and on cell growth. Expression of CARΔGSIV failed to increase the transepithelial resistance in polarized epithelia to the same degree as wild-type CAR and failed to act as a growth modulator in L-cells. Furthermore, we provide evidence for three new CAR interacting partners, including MAGI-1b, PICK1 and PSD-95. CAR appears to interact with several distinct PDZ-domain-containing proteins and may exert its biological function through these interactions.

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

“…Using confocal microscopy and thinsection electron microscopy, hCAR was found to be located at the apical pole of the lateral membrane of polarized epithelial cells, where it colocalizes with ZO-1, the central structural protein of TJs. 20 Moreover, interaction of various PDZ-scaffolding proteins including MUPP-1, 21 MAGI-1b, PICK1 and PSD-95 22 and LNX and LNX-2 23,24 with C-terminal PDZ-motifs was reported. However, the functional aspect of these interactions remains to be elucidated.…”

“…There is growing evidence that hCAR is an important component of interepithelial tight junctions (TJs), suggesting its possible role in cell adhesion and migration. Within the TJs hCAR has been shown to colocalize with known TJ-associated proteins such as zonula occludens-1 (ZO-1), 20 the multi-PDZ-containing proteins MUPP-1, 21 MAGI-1b, PICK1 and PSD-95 22 and LNX and LNX-2. 23,24 A possible functional modulation of cell adhesion is mediated through peptide motifs, which are known to interact with PDZ protein domains, located on the hydrophobic C-terminus of hCAR.…”

PICK1 promotes caveolin-dependent degradation of TGF-β type I receptor

“…Its potential effects on signal transduction and related diseases remain unclear. Recent evidences suggest that PICK1 may affect human cancer development [18,[24][25][26], in which TGF-β signaling has been reported to play significant roles [5].…”

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

“…Later on it was identified as a component of the TJ complex, an interacting partner for a number of other TJ proteins, and a regulator of TJ formation (Cohen et al, 2001;Sollerbrant et al, 2003;Coyne et al, 2004;Excoffon et al, 2004;Mirza et al, 2005;Raschperger et al, 2006). On the basis of in vitro assays, it has been speculated that loss of CAR weakens intercellular adhesion, increases proliferation, and promotes migration as well as invasion of cancer cells (Okegawa et al, 2000Runnebaum, 2003, 2004;Huang et al, 2005;Wang et al, 2005).…”