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.
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.
Arizona Cancer Center, University of Arizona, 1515 N. Campbell Blvd., Tucson, AZ 85724, USA. emay@azcc.arizona.edu
Emmanuelle J
EJ
Meuillet
Daruka
D
Mahadevan
Margareta
M
Berggren
Amy
A
Coon
Garth
G
Powis
D000818:Animals; D015153:Blotting, Western; D004220:Disulfides / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D041681:NIH 3T3 Cells; D051059:PTEN Phosphohydrolase; D011233:Precipitin Tests; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D004220:Disulfides; D025521:Tumor Suppressor Proteins; D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse