A role for the PDZ-binding domain of the coxsackie B virus and adenovirus receptor (CAR) in cell adhesion and growth.
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 (CARDeltaGSIV) 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 CARDeltaGSIV 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.
Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
Katherine J D Ashbourne
KJ
Excoffon
Alesia
A
Hruska-Hageman
Michael
M
Klotz
Geri L
GL
Traver
Joseph
J
Zabner
D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000076122:Disks Large Homolog 4 Protein; D017097:Electric Impedance; D004847:Epithelial Cells / Q000502:physiology*; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007739:L Cells; D008168:Lung / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D011991:Receptors, Virus
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; C091822:Prkcabp protein, mouse; D011991:Receptors, Virus; C033652:postsynaptic density proteins; D051528:Guanylate Kinases