Coxsackie adenovirus receptor (CAR) regulates integrin function through activation of p44/42 MAPK

TY - JOUR

T1 - Coxsackie adenovirus receptor (CAR) regulates integrin function through activation of p44/42 MAPK

AU - Farmer, Charlotte

AU - Morton, Penny E

AU - Snippe, Marjolein

AU - Santis, George

AU - Parsons, Maddy

PY - 2009/9/10

Y1 - 2009/9/10

N2 - 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.

AB - 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.

KW - Adenoviridae

KW - Amino Acid Sequence

KW - Animals

KW - Antigens, CD29

KW - Cell Adhesion

KW - Cell Line, Tumor

KW - Coxsackie and Adenovirus Receptor-Like Membrane Protein

KW - Dimerization

KW - Enzyme Activation

KW - Epithelial Cells

KW - Humans

KW - Integrin beta3

KW - Mitogen-Activated Protein Kinase 1

KW - Mitogen-Activated Protein Kinase 3

KW - Molecular Sequence Data

KW - Protein Conformation

KW - Receptors, Virus

KW - Recombinant Fusion Proteins

KW - Sequence Alignment

KW - Signal Transduction

U2 - 10.1016/j.yexcr.2009.06.008

DO - 10.1016/j.yexcr.2009.06.008

M3 - Article

C2 - 19527712

VL - 315

SP - 2637

EP - 2647

JO - Experimental Cell Research

JF - Experimental Cell Research

IS - 15

ER -