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

Zhen Liu, Huifang M. Zhang, Ji Yuan, Travis Lim, Alhousseynou Sall, Gregory A. Taylor, Decheng Yang

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Interferon-γ-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-κB 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-κB activation. Furthermore, silencing NF-κB with siRNAs significantly inhibited the phosphorylation of FAK and Akt, but not their total expression levels, indicating that NF-κB 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-κB 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-κB functions as a downstream effector and also positively regulates the activity of upstream kinases.

Original languageEnglish (US)
Pages (from-to)1787-1800
Number of pages14
JournalCellular Microbiology
Volume10
Issue number9
DOIs
StatePublished - Aug 11 2008

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Phosphatidylinositol 3-Kinase
Focal Adhesion Protein-Tyrosine Kinases
GTP Phosphohydrolases
Interferons
Chemical activation
Feedback
Transfection
Enterovirus
HeLa Cells
Coxsackievirus Infections
Human Enterovirus B
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphorylation
Phosphatidylinositol 3-Kinases
Cell death
Cell Death
Phosphotransferases
Apoptosis

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

Cite this

Focal adhesion kinase mediates the interferon-γ-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-κB activation. / Liu, Zhen; Zhang, Huifang M.; Yuan, Ji; Lim, Travis; Sall, Alhousseynou; Taylor, Gregory A.; Yang, Decheng.

In: Cellular Microbiology, Vol. 10, No. 9, 11.08.2008, p. 1787-1800.

Research output: Contribution to journalArticle

Liu, Zhen ; Zhang, Huifang M. ; Yuan, Ji ; Lim, Travis ; Sall, Alhousseynou ; Taylor, Gregory A. ; Yang, Decheng. / Focal adhesion kinase mediates the interferon-γ-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-κB activation. In: Cellular Microbiology. 2008 ; Vol. 10, No. 9. pp. 1787-1800.
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abstract = "Interferon-γ-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-κB 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-κB activation. Furthermore, silencing NF-κB with siRNAs significantly inhibited the phosphorylation of FAK and Akt, but not their total expression levels, indicating that NF-κB 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-κB 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-κB functions as a downstream effector and also positively regulates the activity of upstream kinases.",
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