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IRE1α links Nck1 deficiency to attenuated PTP1B expression in HepG2 cells
Hui Li1, Bing Li1, Louise Larose1
1Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
Abstract:
PTP1B, a prototype of the non-receptor subfamily of the protein tyrosine phosphatase superfamily, plays a key role in regulating intracellular signaling from various receptor and non-receptor protein tyrosine kinases. Previously, we reported that silencing Nck1 in human hepatocellular carcinoma HepG2 cells enhances basal and growth factor-induced activation of the PI3K-Akt pathway through attenuating PTP1B expression. However, the underlying mechanism by which Nck1 depletion represses PTP1B expression remains unclear. In this study, we found that silencing Nck1 attenuates PTP1B expression in HepG2 cells through down-regulation of IRE1α. Indeed, we show that silencing Nck1 in HepG2 cells leads to decreased IRE1α expression and signaling. Accordingly, IRE1α depletion using siRNA in HepG2 cells enhances PI3K-dependent basal and growth factor-induced Akt activation, reproducing the effects of silencing Nck1 on activation of this pathway. In addition, depletion of IRE1α also leads to reduced PTP1B expression, which was rescued by ectopic expression of IRE1α in Nck1-depleted cells. Mechanistically, we found that silencing either Nck1 or IRE1α in HepG2 cells decreases PTP1B mRNA levels and stability. However, despite miR-122 levels, a miRNA targeting PTP1B 3' UTR and inducing PTP1B mRNA degradation in HepG2 cells, are increased in both Nck1- and IRE1α-depleted HepG2 cells, a miR-122 antagomir did not rescue PTP1B expression in these cells. Overall, this study highlights an important role for Nck1 in fine-tuning IRE1α expression and signaling that regulate PTP1B expression and subsequent activation of the PI3K-Akt pathway in HepG2 cells.
Insights
Silencing Nck1 in liver cancer cells reduces IRE1α, which lowers PTP1B expression and activates the PI3K-Akt pathway. This reveals a new mechanism for controlling cell signaling.
Area of Science:
- Cellular signaling
- Molecular biology
- Cancer research
Background:
- Protein tyrosine phosphatase 1B (PTP1B) regulates intracellular signaling pathways.
- Nck1 depletion enhances PI3K-Akt pathway activation by reducing PTP1B expression in HepG2 cells.
- The mechanism linking Nck1 depletion to PTP1B repression is currently unknown.
Purpose of the Study:
- To elucidate the mechanism by which Nck1 depletion represses PTP1B expression in hepatocellular carcinoma cells.
- To investigate the role of IRE1α in Nck1-mediated regulation of PTP1B and the PI3K-Akt pathway.
Main Methods:
- Silencing of Nck1 and IRE1α using siRNA in HepG2 cells.
- Analysis of PTP1B and IRE1α expression levels.
- Assessment of PI3K-Akt pathway activation.
- Investigation of mRNA stability and miRNA involvement (miR-122).
Main Results:
- Nck1 silencing decreases IRE1α expression and signaling in HepG2 cells.
- IRE1α depletion mimics Nck1 depletion effects, enhancing Akt activation and reducing PTP1B expression.
- Nck1 and IRE1α depletion reduce PTP1B mRNA stability.
- miR-122 levels increase but do not rescue PTP1B expression upon Nck1/IRE1α depletion.
Conclusions:
- Nck1 fine-tunes IRE1α expression and signaling, which in turn regulates PTP1B expression.
- This Nck1-IRE1α-PTP1B axis controls the PI3K-Akt pathway activation in HepG2 cells.
- The findings provide novel insights into the regulation of hepatocellular carcinoma signaling.
