title: Papillomavirus virus-like particles activate the PI3-kinase pathway via alpha-6 beta-4 integrin upon binding.
abstract: We have previously shown that human papillomavirus virus-like particles (VLPs) are able to activate the Ras/MAP kinase pathway. Ras can also elicit an anti-apoptotic signal via PI3-kinase so we investigated this further. Here we show that binding of VLPs from HPV types 6b, 18, 31, 35 and BPV1 results in activation of PI3-kinase. Activation was achieved by either L1 or L1/L2 VLPs and was dependent on both VLP-cell interaction and correct conformation of the virus particle. VLP-induced PI3-kinase activity resulted in efficient downstream signaling to Akt and consequent phosphorylation of FKHR and GSK3beta. We also present evidence that PV signaling is activated via the alpha6beta4 integrin. These data suggest that papillomaviruses use a common receptor that is able to signal through to Ras. Combined activation of the Ras/MAP kinase and PI3-kinase pathways may be beneficial for the virus by increasing cell numbers and producing an environment more conducive to infection.
authors.affiliation: Cancer Biology Program, Centre for Immunology and Cancer Research, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fothergill
authors.forename: Nigel A J
authors.initials: NA
authors.lastname: McMillan
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D052688:Bovine papillomavirus 1 / Q000472:pathogenicity* / Q000502:physiology; D002417:Cattle; D002453:Cell Cycle; D002460:Cell Line; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D039161:Integrin alpha6beta4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D027383:Papillomaviridae / Q000472:pathogenicity* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014771:Virion / Q000472:pathogenicity / Q000502:physiology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D039161:Integrin alpha6beta4; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3