20980511
not annotated - annotated - LINNAEUS only
Dominant inhibition of Akt/protein kinase B signaling by the matrix protein of a negative-strand RNA virus.
Vesicular stomatitis virus (VSV) is a rhabdovirus that alters host nuclear and cytoplasmic function upon infection. We have investigated the effect of VSV infection on cellular signaling through the phosphatidylinositol-3 kinase (PI3k)/Akt signaling pathway. Akt phosphorylation at both threonine 308 (Thr308) and serine 473 (Ser473) was inhibited in cells infected with VSV. This inhibition was rapid (beginning within the first 2 to 3 h postinfection) and correlated with the dephosphorylation of downstream effectors of Akt, such as glycogen synthase kinase 3Beta (GSK3Beta) and mammalian target of rapamycin (mTOR). The dephosphorylation of Akt occurred in the presence of growth factor stimulation and was not overcome through constitutive membrane targeting of Akt or high levels of phosphatidylinositol-3,4,5-triphosphate (PIP3) accumulation in the membrane. Akt dephosphorylation was not a result of alterations in PDK1 phosphorylation or activity, changes in phosphatase and tensin homologue deleted on chromosome 10 (PTEN) levels, or the downregulation of PI3k signaling. Inactivation of Akt was caused by the expression of the viral M protein in the absence of other viral components, and an M protein mutant that does not inhibit RNA polymerase II (Pol II) transcription and nuclear/cytoplasmic transport was also defective in inhibiting Akt phosphorylation. These data illustrate that VSV utilizes a novel mechanism to alter this central player in cell signaling and oncogenesis. It also suggests an inside-out model of signal transduction where VSV interruption of nuclear events has a rapid and significant effect on membrane signaling events.
Ann file
T1 Species 110 136 Vesicular stomatitis virus
N1 Reference T1 Taxonomy:11276
T2 Species 138 141 VSV
N2 Reference T2 Taxonomy:11276
T3 Species 261 264 VSV
N3 Reference T3 Taxonomy:11276
T4 Species 481 484 VSV
N4 Reference T4 Taxonomy:11276
T5 Species 1508 1511 VSV
N5 Reference T5 Taxonomy:11276
T6 Species 1669 1672 VSV
N6 Reference T6 Taxonomy:11276