In:
American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 292, No. 4 ( 2007-04), p. C1339-C1352
Abstract:
Focal adhesion kinase (FAK) is important to cellular functions such as proliferation, migration, and survival of anchorage-dependent cells. We investigated the role of FAK in modulating normal cellular responses, specifically cell survival in response to inflammatory stimuli and serum withdrawal, using FAK-knockout (FAK −/− ) embryonic fibroblasts. FAK −/− fibroblasts were more vulnerable to TNF-α-induced apoptosis, as measured by terminal deoxynucleotidyl transferase positivity. FAK −/− fibroblasts also demonstrated increased procaspase-3 cleavage to p17 subunit, whereas this was undetectable in FAK +/+ fibroblasts. Insulin receptor substrate-1 expression was completely abolished and NF-κB activity was reduced, with a concomitant decrease in abundance of the anti-apoptotic protein Bcl-x L in FAK −/− cells. Upon serum withdrawal, FAK +/+ cells exhibited marked attenuation of basal ERK phosphorylation, while FAK −/− cells, in contrast, maintained high basal ERK phosphorylation. Moreover, inhibition of ERK phosphorylation potentiated serum withdrawal-induced caspase-3 activity. This was paralleled by increased insulin receptor substrate (IRS)-2 expression in FAK −/− cells, although both insulin- and IGF-1-mediated phosphorylation of Akt/PKB and GSK-3 were impaired. This suggests that IRS-2 protects against apoptosis upon serum withdrawal via the ERK signaling pathway. The specific role of FAK to protect cells from apoptosis is regulated by activation and phosphorylation of NF-κB and interaction between activated growth factor anti-apoptotic signaling pathways involving both phosphatidylinositol 3-kinase/Akt and MAPK/ERK1/2. We demonstrate that FAK is necessary for upregulation of the anti-apoptotic NF-κB response, as well as for normal expression of growth factor signaling proteins. Thus we propose a novel role for FAK in protection from cytokine-mediated apoptosis.
Type of Medium:
Online Resource
ISSN:
0363-6143
,
1522-1563
DOI:
10.1152/ajpcell.00144.2006
Language:
English
Publisher:
American Physiological Society
Publication Date:
2007
detail.hit.zdb_id:
1477334-X
SSG:
12
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