Download the full-sized PDF of Herpes Simplex Virus Requires VP11/12 to Activate Src Family Kinase-PI3 Kinase-Akt SignallingDownload the full-sized PDF



Permanent link (DOI):


Export to: EndNote  |  Zotero  |  Mendeley


This file is in the following communities:

Graduate Studies and Research, Faculty of


This file is in the following collections:

Theses and Dissertations

Herpes Simplex Virus Requires VP11/12 to Activate Src Family Kinase-PI3 Kinase-Akt Signalling Open Access


Other title
PI3 Kinase
Type of item
Degree grantor
University of Alberta
Author or creator
Wagner, Melany
Supervisor and department
Smiley, James (Medical Microbiology and Immunology)
Examining committee member and department
Smiley, James (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
This thesis defines a novel role for the Herpes Simplex Virus (HSV) tegument protein, virion protein (VP) 11/12 as a modulator of host cell signalling. Studies aimed at examining infection induced lymphocyte inactivation, revealed that VP11/12 is tyrosine phosphorylated in three lymphocyte lineages (T cell, B cell and NK cell) following exposure to HSV-1 or HSV-2 infected fibroblasts. Tyrosine phosphorylation of VP11/12 was greater in lymphocytes compared to fibroblasts or epithelial cells and phosphorylation was enhanced by the lymphocyte specific Src family kinase (SFK) Lck during transfection- or infection-based assays. This suggested that VP11/12 is a substrate of Lck or a kinase activated by Lck. Lck is best known for initiating intracellular signalling downstream of the T cell receptor (TCR) and NK cell receptors. However, VP11/12 null HSV mutants retained the ability to block TCR signalling and NK cell cytotoxicity. Phosphorylation of VP11/12 occurred in the absence of any known Lck stimulus, like TCR ligation. Infection alone may activate Lck since Lck in infected Jurkat cells displayed features characteristic of activation: a reduced electrophoretic mobility in sodium dodecyl sulphate polyacrylamide gel and a marked increase in phosphorylation at the activation loop tyrosine (Y394). SFK substrates sometimes activate their cognate kinase through high affinity binding of the SFK Src homology (SH) 2 or SH3 domains. VP11/12 may serve this dual function since it interacts with Lck or Lck signalling complexes and is strictly required for Lck activation during infection. SFKs including Lck lie upstream of the canonical phosphoinositide 3-kinase (PI3K)-Akt pathway in signalling emanating from immune receptors, growth factor receptors and polyoma middle T antigen (MTAg). In HSV infection of Jurkat T cells and human embryonic lung fibroblasts, we find that VP11/12 interacts with PI3K either directly or indirectly and is required for infection induced activation of the PI3K-Akt signalling pathway. SFK activity is required for tyrosine phosphorylation of VP11/12, VP11/12-PI3K interactions, and Akt activation in infected fibroblasts. This data suggests that VP11/12 orchestrates signalling analogous to that of MTAg. In this model, VP11/12 activates SFKs to induce its own phosphorylation, subsequently allowing for interactions with PI3K and activation of Akt.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication

File Details

Date Uploaded
Date Modified
Audit Status
Audits have not yet been run on this file.
File format: pdf (Portable Document Format)
Mime type: application/pdf
File size: 3084950
Last modified: 2015:10:12 13:36:08-06:00
Filename: Wagner_Melany_Fall2010.pdf
Original checksum: 822f8d1a80596b421e690de71ce31b7c
Well formed: false
Valid: false
Status message: Invalid page tree node offset=613024
Status message: Unexpected error in findFonts java.lang.ClassCastException: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject cannot be cast to edu.harvard.hul.ois.jhove.module.pdf.PdfDictionary offset=3138
Status message: Invalid Annotation list offset=3040365
Status message: Invalid outline dictionary item offset=3050087
Activity of users you follow
User Activity Date