Phosphorylation of Tyrosine 568 Controls Nuclear Export of Nrf2

Nuclear factor Nrf 2, under normal conditions, is retained in the cytosol by INrf 2. Antioxidants and oxidants antagonize this interaction, resulting in the release of Nrf 2. Nrf 2 translocates to the nucleus binds to ARE and activates a battery of chemopreventive genes. Once this is achieved, Nrf 2...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2006-04, Vol.281 (17), p.12132-12142
Main Authors: Jain, Abhinav K., Jaiswal, Anil K.
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Line, Tumor
Cell Nucleus - chemistry
Cell Nucleus - metabolism
Exportin 1 Protein
Humans
Hydrogen Peroxide - pharmacology
Immunoblotting
Immunoprecipitation
Karyopherins
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Mutation - genetics
NF-E2-Related Factor 2 - antagonists & inhibitors
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Phosphorylation
Protein Transport
Protein Tyrosine Phosphatases - metabolism
Proto-Oncogene Proteins c-fyn - metabolism
Receptors, Cytoplasmic and Nuclear
RNA, Small Interfering - pharmacology
src-Family Kinases - metabolism
Tyrosine - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nuclear factor Nrf 2, under normal conditions, is retained in the cytosol by INrf 2. Antioxidants and oxidants antagonize this interaction, resulting in the release of Nrf 2. Nrf 2 translocates to the nucleus binds to ARE and activates a battery of chemopreventive genes. Once this is achieved, Nrf 2 is exported out of the nucleus, binds with INrf 2, and degrades. Nrf 2 contains well defined signals that control nuclear import and export of Nrf 2. The present studies demonstrate that phosphorylation of tyrosine 568 is required for Crm1-mediated nuclear export and degradation of Nrf 2. Mutation of tyrosine 568 to alanine and phenylalanine resulted in the loss of interaction with Crm1 and abrogation of nuclear export of Nrf 2. Nrf 2Y568A is deficient in nuclear export and displays delayed degradation compared with wild-type Nrf 2. In addition, Src inhibitor PP2 caused nuclear accumulation of Nrf 2 in normal and hydrogen peroxide-treated cells but had no effect on localization of mutant Nrf 2Y568A. Further experiments with small interfering RNA revealed that Fyn phosphorylated Nrf 2Y568 leading to nuclear export and degradation of Nrf 2.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M511198200