title: Role of Herpes simplex virus 1 VP11/12 tyrosine-based binding motifs for Src family kinases, p85, Grb2 and Shc in activation of the phosphoinositide 3-kinase-Akt pathway.
abstract: The abundant HSV-1 tegument protein VP11/12 encoded by gene UL46 is essential for induction of the PI3K/Akt-signaling pathway during infection. VP11/12 utilizes tyrosine-based motifs within its C-terminal region to bind the SH2 domains of Src family kinases, the p85 subunit of PI3 Kinase and Grb2, and the PTB domain of Shc. We previously proposed that the interaction with SFKs and p85 is used to gain control over the PI3K/Akt signaling pathway. We tested this model by evaluating the effects of mutations that eliminate each of these interactions on the ability of HSV-1 to activate Akt. Inhibiting the interaction of VP11/12 with SFKs, p85 and Grb2 reduced Akt activation, while inhibiting the interaction with Shc had little effect. Overall these data support the suggestion that VP11/12 stimulates the PI3K/Akt pathway by mimicking an activated growth factor receptor.
authors.affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G2H7.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Strunk
authors.affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G2H7.
authors.forename: Daniel Gomez
authors.initials: DG
authors.lastname: Ramos
authors.affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G2H7.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Saffran
authors.affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G2H7. Electronic address: jsmiley@ualberta.ca.
authors.forename: James R
authors.initials: JR
authors.lastname: Smiley
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006561:Herpes Simplex / Q000378:metabolism* / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; D051380:GRB2 Adaptor Protein; C414831:UL46 protein, Human herpesvirus 1; D014764:Viral Proteins; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Herpesvirus; PI3 kinase; Signaling; Src family kinase; Tegument