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.

Abstract

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.

• Authors: Emmanuelle J Meuillet, Daruka Mahadevan, Margareta Berggren, Amy Coon, Garth Powis
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 429 Issue 2 Pg. 123-33 (Sep 15 2004) ISSN: 0003-9861 [Print] United States
• PMID: 15313215 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Disulfides
• Tumor Suppressor Proteins
• Thioredoxins
• Thioredoxin-Disulfide Reductase
• Protein Tyrosine Phosphatases
• PTEN Phosphohydrolase
• Pten protein, mouse

Topics

• Animals
• Blotting, Western
• Disulfides (metabolism)
• Lipid Metabolism
• Mice
• Models, Molecular
• Mutagenesis, Site-Directed
• NIH 3T3 Cells
• PTEN Phosphohydrolase
• Precipitin Tests
• Protein Binding
• Protein Tyrosine Phosphatases (chemistry, genetics, metabolism)
• Thioredoxin-Disulfide Reductase (metabolism)
• Thioredoxins (antagonists & inhibitors, metabolism)
• Tumor Suppressor Proteins (chemistry, genetics, metabolism)