Thioredoxin-1 binds to the C2 domain of PTEN inhibiting PTEN's lipid phosphatase activity and membrane binding: a mechanism for the functional loss of PTEN's tumor suppressor activity

• Published in: Archives of biochemistry and biophysics 2004-09, Vol.429 (2), p.123-133
• Main Authors: Meuillet, Emmanuelle J, Mahadevan, Daruka, Berggren, Margareta, Coon, Amy, Powis, Garth
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Cancer; Disulfides - metabolism; Lipid Metabolism; Mice; Models, Molecular; Mutagenesis, Site-Directed; NIH 3T3 Cells; Precipitin Tests; Protein Binding; Protein Tyrosine Phosphatases - chemistry; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; PTEN; PTEN Phosphohydrolase; Redox control; Thioredoxin; Thioredoxin-Disulfide Reductase - metabolism; Thioredoxins - antagonists & inhibitors; Thioredoxins - metabolism; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2004.04.020

Thioredoxin-1 (Trx-1) is a 12 kDa redox protein that is overexpressed in a large number of human tumors. Elevated Trx-1 is associated with increased tumor cell proliferation, inhibited apoptosis, aggressive tumor growth, and decreased patient survival. The molecular mechanisms for the promotion of tumorigenesis by Trx-1 are not known. PTEN is a major tumor suppressor of human cancer that acts by hydrolyzing membrane phosphatidylinositol (PtdIns)-3-phosphates, thus, preventing the activation of the survival signaling kinase Akt by PtdIns-3-kinase. We show that Trx-1 binds in a redox dependent manner to PTEN to inhibit its PtdIns-3-phosphatase activity which results in increased Akt activation in cells. Molecular docking and site-specific mutation studies show that the binding of Trx-1 to PTEN occurs through a disulfide bond between the active site Cys 32 of Trx-1 and Cys 212 of the C2 domain of PTEN leading to steric interference by bound Trx-1 of the catalytic site of PTEN and of the C2 lipid membrane-binding domain. The results of the study suggest that the increased levels of Trx-1 in human tumors could lead to functional inhibition of PTEN tumor suppressor activity providing an additional mechanism for tumorigenesis with loss of PTEN activity.