title: Opposite effects of HIV-1 p17 variants on PTEN activation and cell growth in B cells.
abstract: The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH(2)-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyze the signal transduction pathways induced by p17/p17R interaction and show that in Raji cells, a human B cell line stably expressing p17R on its surface, p17 induces a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2 and downregulate pAkt, which are the major intracellular signalling components involved in AP-1 activation. These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serine/threonine (Ser/Thr) kinase ROCK. Indeed, the COOH-terminal truncated form of p17 (p17Δ36) induced activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we show that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggers an activation of PI3K/Akt signalling pathway, and leads to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the COOH-terminal region in modulating the p17 signalling pathways so highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant mimicking the p17Δ36-induced signalling in B cells and displaying the capacity of promoting B cell growth and tumorigenesis.
authors.affiliation: Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.forename: Stefania
authors.initials: S
authors.lastname: Marsico
authors.forename: Anna K
authors.initials: AK
authors.lastname: Magiera
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Bruno
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism*; D009994:Osmolar Concentration; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D012996:Solutions; D018808:Transcription Factor AP-1 / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D015488:HIV Antigens; D050505:Mutant Proteins; D011991:Receptors, Virus; D012996:Solutions; D018808:Transcription Factor AP-1; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human