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

Emmanuelle J. Meuillet, Daruka Mahadevan, Margareta Berggren, Amy Coon, Garth Powis

Producción científica: Articlerevisión exhaustiva

170 Citas (Scopus)

Resumen

Thioredoxin-1 (Trx-1) is a 12kDa 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 Cys32 of Trx-1 and Cys212 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.

Idioma originalEnglish (US)
Páginas (desde-hasta)123-133
Número de páginas11
PublicaciónArchives of Biochemistry and Biophysics
Volumen429
N.º2
DOI
EstadoPublished - sept 15 2004
Publicado de forma externa

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Biochemistry

Huella

Profundice en los temas de investigación de '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'. En conjunto forman una huella única.

Citar esto