title: Focal adhesion kinase mediates cell survival via NF-kappaB and ERK signaling pathways.
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-alpha-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-kappaB 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-kappaB 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-kappaB 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.
authors.affiliation: West Los Angeles Veterans Administration Medical Center, Los Angeles, CA, USA.
authors.forename: Danshan
authors.initials: D
authors.lastname: Huang
authors.forename: Michelle
authors.initials: M
authors.lastname: Khoe
authors.forename: Merone
authors.initials: M
authors.lastname: Befekadu
authors.forename: Sue
authors.initials: S
authors.lastname: Chung
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takata
authors.forename: Dusko
authors.initials: D
authors.lastname: Ilic
authors.forename: Michael
authors.initials: M
authors.lastname: Bryer-Ash
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: D016895:Culture Media, Serum-Free; D005419:Flavonoids; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one