Focal Adhesion Kinase Activates NF-κB via the ERK1/2 and p38MAPK Pathways in Amyloid-β25-35-Induced Apoptosis in PC12 Cells

Abstract

Increasing evidence supports that amyloid plaques, comprised of amyloid-β (Aβ), are a key feature of Alzheimer's disease (AD). But the mechanism of Aβ in AD is not yet fully understood. Previous studies have demonstrated that in Aβ-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-κB) is activated. Meanwhile, focal adhesion kinase (FAK) is also activated. However, the relationship between NF-κB and FAK remains unclear. Using differentiated PC12 cells, we investigated this relationship in Aβ(25-35)-induced apoptosis. The results showed that FAK phosphorylation increased at 6-9 hours after Aβ treatment, slightly shorter than the activation of NF-κB (6-12 hours). In this process, both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation levels were increased. After FAK expression was inhibited by its siRNA, the activities of ERK1/2, p38MAPK, and NF-κB were all suppressed. When ERK1/2 and p38MAPK expressions were inhibited by their siRNAs respectively, NF-κB activity was also suppressed. But FAK phosphorylation was not affected. When NF-κB expression was inhibited, all of the phosphorylation levels of FAK, ERK1/2, and p38MAPK were not affected. These phenomena indicated that FAK is upstream of ERK1/2, p38MAPK, and NF-κB, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-κB. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with IκB kinase. Taken together, our results suggest that FAK activates NF-κB via ERK1/2 and p38MAPK pathways in Aβ(25-35)-induced apoptosis of differentiated PC12 cells.

NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar

“…It is possible that activation of PDGFRβ, via activation of Erk1/2 and Erk5, promotes the nuclear localization of NF-κB, which increases the transcription of NR4A1. The finding that in amyloid plaques Erk1/2 is activated and directly interacts with IκB kinase promoting NF-κB activation [52] , is consistent with this possibility.…”

MLK3‐MKK3/6‐P38MAPK cascades following N‐methyl‐D‐aspartate receptor activation contributes to amyloid‐β peptide‐induced apoptosis in SH‐SY5Y cells

“…Suppression of NF‐κB activation provides neuroprotection against Aβ1–42‐dependent neurotoxicity (Yu et al, ). Moreover, NF‐κB activation is mediated by focal adhesion kinase and subsequent extracellular signal‐regulated kinase (ERK) 1/2 and P38MAPK during Aβ25–35‐induced PC12 cell apoptosis (Wang et al, ). Collectively, NF‐κB might be another target for treatment of AD.…”

Breast Cancer Malignant Processes are Regulated by Pax-5 Through the Disruption of FAK Signaling Pathways

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