Linked Life Data

18701889

Source:http://linkedlifedata.com/resource/pubmed/id/18701889

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7211
pubmed:dateCreated
2008-9-18
pubmed:abstractText
Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling. The mechanisms facilitating viral entry and gene expression are not clearly understood. Here we show that platelet-derived growth factor-alpha receptor (PDGFR-alpha) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-alpha associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-alpha was genetically deleted or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-alpha blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-alpha was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-alpha, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit HCMV-induced PDGFR-alpha phosphorylation. Taken together, these data indicate that PDGFR-alpha is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1476-4687
pubmed:author
pubmed:issnType
Electronic
pubmed:day
18
pubmed:volume
455
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
391-5
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:18701889-Animals, pubmed-meshheading:18701889-Cell Line, pubmed-meshheading:18701889-Cytomegalovirus, pubmed-meshheading:18701889-Cytomegalovirus Infections, pubmed-meshheading:18701889-Enzyme Activation, pubmed-meshheading:18701889-Gene Expression Regulation, Viral, pubmed-meshheading:18701889-Humans, pubmed-meshheading:18701889-Mice, pubmed-meshheading:18701889-Phosphatidylinositol 3-Kinases, pubmed-meshheading:18701889-Phosphorylation, pubmed-meshheading:18701889-Phosphotyrosine, pubmed-meshheading:18701889-Platelet-Derived Growth Factor, pubmed-meshheading:18701889-Protein Binding, pubmed-meshheading:18701889-Proto-Oncogene Proteins c-akt, pubmed-meshheading:18701889-Receptor, Platelet-Derived Growth Factor alpha, pubmed-meshheading:18701889-Signal Transduction, pubmed-meshheading:18701889-Viral Envelope Proteins, pubmed-meshheading:18701889-Virus Internalization
pubmed:year
2008
pubmed:articleTitle
Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection.
pubmed:affiliation
Department of Neurosciences, California Pacific Medical Center Research Institute, Suite 220, 475 Brannan Street, San Francisco, California 94107, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't