title: 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.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, The James Hogg iCAPTURE Center - St. Paul's Hospital, Vancouver, Canada.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Huifang M
authors.initials: HM
authors.lastname: Zhang
authors.forename: Ji
authors.initials: J
authors.lastname: Yuan
authors.forename: Travis
authors.initials: T
authors.lastname: Lim
authors.forename: Alhousseynou
authors.initials: A
authors.lastname: Sall
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Decheng
authors.initials: D
authors.lastname: Yang
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003384:Coxsackievirus Infections / Q000201:enzymology* / Q000821:virology; D029822:Enterovirus B, Human; D025461:Feedback, Physiological; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D009205:Myocarditis / Q000201:enzymology / Q000821:virology; D009206:Myocardium / Q000201:enzymology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D016328:NF-kappa B; C113183:FAK-related nonkinase; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C101131:Igtp protein, mouse