Focal adhesion kinase mediates the interferon-gamma-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-kappaB activation.

Published

Journal Article

Interferon-gamma-inducible GTPase (IGTP) expression is upregulated in coxsackievirus B3 (CVB3)-infected murine heart and inhibits CVB3-induced apoptosis through activation of the PI3 kinase/Akt pathway. However, the mechanism of this pathway activation is unknown. In this study, using doxcycycline-inducible Tet-On HeLa cells that overexpress IGTP, we have demonstrated that focal adhesion kinase (FAK) is phosphorylated in response to IGTP expression and that transfection of the Tet-On HeLa cells with a dominant negative FAK (FRNK) blocks Akt activation. Furthermore, induction of IGTP also promoted the NF-kappaB activation as evidenced by its enhanced nuclear translocation, binding to transcriptional promoters and increased transcriptional activity. However, FRNK transfection and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both blocked the IGTP-induced translocation and NF-kappaB activation. Furthermore, silencing NF-kappaB with siRNAs significantly inhibited the phosphorylation of FAK and Akt, but not their total expression levels, indicating that NF-kappaB activation is required for the IGTP-induced activation of FAK and PI3K/Akt. Finally, blocking this survival pathway by transfection of FRNK or silencing of NF-kappaB reduced CVB3 replication and enhanced cell death during CVB3 infection. Taken together, these results suggest that FAK is a mediator upstream of PI3K/Akt and NF-kappaB functions as a downstream effector and also positively regulates the activity of upstream kinases.

Full Text

Duke Authors

Cited Authors

  • Liu, Z; Zhang, HM; Yuan, J; Lim, T; Sall, A; Taylor, GA; Yang, D

Published Date

  • September 2008

Published In

Volume / Issue

  • 10 / 9

Start / End Page

  • 1787 - 1800

PubMed ID

  • 18452580

Pubmed Central ID

  • 18452580

Electronic International Standard Serial Number (EISSN)

  • 1462-5822

Digital Object Identifier (DOI)

  • 10.1111/j.1462-5822.2008.01165.x

Language

  • eng

Conference Location

  • England