CFTR interacts with Hsp90 and regulates the phosphorylation of AKT and ERK1/2 in colorectal cancer cells.

Kaisheng Liu,Weiqing Wu,Yong Dai,Zhifan Zhou,Yaomin Guo,Yong Wan,Pan Zhao,Hongtao Jin,Zhiqiang Cheng,Ying Liu,Maolin Wang,Chang Zou,Jianhong Wang

doi:10.1002/2211-5463.12641

Abstract

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF cells and tissues exhibit various mitochondrial abnormalities. However, the underlying molecular mechanisms remain elusive. Here, we examined the mechanisms through which CFTR regulates Bcl‐2 family proteins, which in turn regulate permeabilization of the mitochondrial outer membrane. Notably, inhibition of CFTR activated Bax and Bad, but inhibited Bcl‐2. Moreover, degradation of phosphorylated extracellular signal‐regulated kinase 1/2 (ERK1/2) and AKT increased significantly in CFTR‐knockdown cells. Dysfunction of CFTR decreased heat‐shock protein 90 (Hsp90) mRNA levels, and CFTR was found to interact with Hsp90. Inhibition of Hsp90 by SNX‐2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco2 and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF‐related diseases.

Highlights

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
The results showed that CFTR was significantly downregulated (Fig. 1A)
We built a model of the protein–protein interaction with PyMOL to predict the complex (Fig. 3C). These results indicated that degradation of phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) and phospho-AKT in CFTR-knockdown cells might be associated with decreased heat-shock protein 90 (Hsp90) expression

Summary

Introduction

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Degradation of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT increased significantly in CFTR-knockdown cells. Inhibition of Hsp by SNX-2112 induced the degradation of phosphorylated AKT and ERK1/2 in Caco and HRT18 cells. These findings may help provide insights into the physiological role of CFTR in CF-related diseases. Cystic fibrosis (CF) is an autosomal recessive genetic disease that is most common in Caucasians that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [1]. Abbreviations CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; ERK1/2, extracellular signal-regulated kinase 1/2; Hsp, heat-shock protein 90; shRNA, short hairpin RNA; DF508, deletion of the phenylalanine at position 508.

Objectives

Methods

Conclusion