Open AccessFocal 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
Author(s) -
Liu Zhen,
Zhang Huifang M.,
Yuan Ji,
Lim Travis,
Sall Alhousseynou,
Taylor Gregory A.,
Yang Decheng
Publication year - 2008
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2008.01165.x
Subject(s) - protein kinase b , biology , pi3k/akt/mtor pathway , focal adhesion , microbiology and biotechnology , kinase , transfection , gene silencing , phosphatidylinositol , small interfering rna , cancer research , signal transduction , wortmannin , ly294002 , cell culture , biochemistry , gene , genetics
Summary 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.