title: Coxsackie adenovirus receptor (CAR) regulates integrin function through activation of p44/42 MAPK.
abstract: The coxsackie B virus and adenovirus receptor (CAR) is an attachment receptor for Adenovirus serotype 5 (Ad5) and in many cell types forms homodimers with neighbouring cells as part of a cell adhesion complex. CAR co-operates with cell surface integrin receptors to enable efficient viral entry, but little is known about the mechanism of crosstalk between these two receptor types. Here we show that overexpression of CAR in human epithelial cells leads to increased basal activation of p44/42 MAPK and this is required for efficient Ad5 infection. We demonstrate that CAR forms homodimers in cis and that this dimerisation is enhanced in the presence of Ad5 in a phospho-p44/42-dependent manner. CAR-induced p44/42 activation also leads to increased activation of beta1 and beta3 integrins. Analysis of CAR mutants demonstrates that the cyto domain of CAR is required for CAR-induced p44/42 activation, integrin activation and localisation to cell junctions. This data for the first time demonstrates that signalling downstream of CAR can have a dual effect on integrins and CAR itself in order to promote efficient viral binding to cell membranes.
authors.affiliation: Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, 5th Floor Tower Wing, Guy's Hospital Campus, London, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Farmer
authors.forename: Penny E
authors.initials: PE
authors.lastname: Morton
authors.forename: Marjolein
authors.initials: M
authors.lastname: Snippe
authors.forename: George
authors.initials: G
authors.lastname: Santis
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
mesh_terms: D000256:Adenoviridae / Q000378:metabolism / Q000472:pathogenicity; D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019281:Dimerization; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011991:Receptors, Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology
chemical_list: C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019012:Integrin beta1; D039661:Integrin beta3; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3