title: Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness.
abstract: Given our previous findings that human cytomegalovirus (HCMV) nucleic acids and proteins are expressed in human malignant glioma in vivo, we investigated cellular signaling events associated with HCMV infection of human glioma and astroglial cells. HCMV infection caused rapid activation of the phosphatidylinositol-3 kinase (PI-3K) effector AKT kinase in human astro-glial and fibroblast cells, and induced tyrosine phosphorylation of phospholipase Cgamma (PLCgamma). Co-immunoprecipitation experiments revealed association of the p85 regulatory subunit of PI-3K with a high-molecular weight protein phosphorylated on tyrosine, following short-term exposure to HCMV. In contrast to a previous report, we were unable to confirm the identity of this high-molecular weight protein as being the epidermal growth factor receptor (EGFR). Stimulation of glioma and fibroblast cell lines over-expressing EGFR with HCMV (whole virus) or soluble glycoprotein B did not induce tyrosine phosphorylation of the receptor, as did the genuine ligand, EGF. Furthermore, we found that expression levels of the human ErbB1-4 receptors were not rate-limiting for HCMV infection. Dispensability of EGFR function during early HCMV infection was substantiated by demonstration of viral immediate early gene expression in cells lacking the EGFR gene, indicating that HCMV may promote oncogenic signaling pathways independently of EGFR activation. Among non-receptor cellular kinases, HCMV infection induced phosphorylation of focal adhesion kinase (FAK) Tyr397, which is indispensable for integrin-mediated cell migration and invasion. HCMV-induced FAK activation was paralleled by increased extracellular matrix-dependent migration of human malignant glioma but not normal astro-glial cells, suggesting that HCMV can selectively augment glioma cell invasiveness.
authors.affiliation: Department of Surgery, University of Alabama School of Medicine, Birmingham, AL, USA. charles.cobbs@gmail.com
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cobbs
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
authors.forename: Scott
authors.initials: S
authors.lastname: Denham
authors.forename: Wenyue
authors.initials: W
authors.lastname: Zhang
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
authors.forename: Russ
authors.initials: R
authors.lastname: Pieper
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Kraus
mesh_terms: D001253:Astrocytes / Q000201:enzymology / Q000821:virology; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003587:Cytomegalovirus / Q000472:pathogenicity; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt