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 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.
Jain
Abhinav K
AK
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Jaiswal
Anil K
AK
D021581:Active Transport, Cell Nucleus; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D047468:Immunoprecipitation; D028884:Karyopherins; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism; D000097606:Exportin 1 Protein
D006861:Hydrogen Peroxide; D028884:Karyopherins; D051267:NF-E2-Related Factor 2; D017027:Protein Tyrosine Phosphatases; D051076:Proto-Oncogene Proteins c-fyn; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014443:Tyrosine; D019061:src-Family Kinases; D000097606:Exportin 1 Protein