Induced focal adhesion kinase expression suppresses apoptosis by activating NF-kappaB signaling in intestinal epithelial cells.
Focal adhesion kinase (FAK) integrates various extracellular and intracellular signals and is implicated in a variety of biological functions, but its exact role and downstream targeting signals in the regulation of apoptosis in intestinal epithelial cells (IECs) remains unclear. The current study tested the hypothesis that FAK has an antiapoptotic role in the IEC-6 cell line by altering NF-kappaB signaling. Induced FAK expression by stable transfection with the wild-type (WT)-FAK gene increased FAK phosphorylation, which was associated with an increase in NF-kappaB activity. These stable WT-FAK-transfected IECs also exhibited increased resistance to apoptosis when they were exposed to TNF-alpha plus cycloheximide (TNF-alpha/CHX). Specific inhibition of NF-kappaB by the recombinant adenoviral vector containing the IkappaBalpha superrepressor prevented increased resistance to apoptosis in WT-FAK-transfected cells. In contrast, inactivation of FAK by ectopic expression of dominant-negative mutant of FAK (DNM-FAK) inhibited NF-kappaB activity and increased the sensitivity to TNF-alpha/CHX-induced apoptosis. Furthermore, induced expression of endogenous FAK by depletion of cellular polyamines increased NF-kappaB activity and resulted in increased resistance to TNF-alpha/CHX-induced apoptosis, both of which were prevented by overexpression of DNM-FAK. These results indicate that increased expression of FAK suppresses TNF-alpha/CHX-induced apoptosis, at least partially, through the activation of NF-kappaB signaling in IECs.
Zhang
Huifang M
HM
Dept. of Surgery, Baltimore Veterans Affairs Medical Center, 10 N. Greene St., Baltimore, MD 21201, USA.
Keledjian
Kaspar M
KM
Rao
Jaladanki N
JN
Zou
Tongtong
T
Liu
Lan
L
Marasa
Bernard S
BS
Wang
Shelley R
SR
Ru
Lisa
L
Strauch
Eric D
ED
Wang
Jian-Ying
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051417:Focal Adhesion Kinase 1; C496052:Ptk2 protein, rat