Activating transcription factor 6 protects insulin receptor from ER stress-stimulated desensitization via p42/44 ERK pathway.

ABSTRACT:

Aim

Activating transcription factor 6 (ATF6) is a key signal transducer of endoplasmic reticulum stress (ER stress). This study was conducted to clarify the potential role of ATF6 in the insulin signaling pathway under chronic ER stress.

Methods

ER stress of HEK293 cells was induced with tunicamycin (2 ?g/mL). The cells were transfected with ATF6? or ATF6?. The phosphorylation level of insulin receptor (IR) was analyzed using Western blot. The changes in ER stress and ERK signaling pathways were explored using Western blot and quantitative real-time PCR.

Results

Tunicamycin-induced chronic ER stress attenuated IR tyrosine phosphorylation in a time-dependent manner, whereas over-expression of ATF6 protected IR from desensitization. ATF6 modulation of IR suppression was associated with insulin-stimulated extracellular signal-regulated kinase (ERK) phosphorylation. The treatment of the cells with a specific ERK inhibitor U0126 (10 ?mol/L) mimicked the effect of ATF6 over-expression and restored the insulin-stimulated IR phosphorylation. The treatment of the cells with the ERK activator epidermal growth factor (EGF, 200 ng/mL) decreased the protection effect of ATF6 on IR.

Conclusion

Our results demonstrate that ATF6 may serve as a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes.

SUBMITTER: Tang X 

PROVIDER: S-EPMC4003301 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature