DESCRIPTION (provided by applicant): Regulation of PTEN activity and translocation in normal and cancer cells. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a recently identified tumor suppressor, which is deleted/mutated in human tumors including glioblastomas, carcinomas of the prostate, uterus, bladder and breast and malignant melanomas. PTEN dephosphorylates the 3-position of phosphatidylinositol (Pdtlns)-3-phosphates, thus, preventing activation of Akt by Ptdlns-3-kinase. PTEN also dephosphorylates focal adhesion kinase (p125FAK) and Shc, a SH2-phosphotyrosine-binding adapter protein that links tyrosine kinases to Ras signaling and the MAP kinase pathway. PTEN contains a C2 lipid binding domain at its C-terminal end, which is responsible for its' binding to phosphatidylcholine at the inner leaflet of the plasma membrane in a Ca2+-independent manner. It has been suggested that this domain may influence the activity of the protein, but no clear-cut role for the C2 domain of PTEN has been proposed.We have recently found that a small redox protein, thioredoxin, binds directly to the C2 domain of PTEN and thereby is able to negatively regulate the lipid activity of PTEN. Thioredoxin binds to the Cys212 of PTEN forming a stable complex, which can be regulated in a redox dependent manner. Moreover, the addition of selenium to cells, which is know to increase thioredoxin reductase activity, is able to restore PTEN activity.Hence, the hypotheses upon which our studies are based are that 1) PTEN activity is allosterically regulated by a small redox protein and indirectly by selenium and that 2) PTEN activity can be regulated indirectly by its C2 domain. The objectives of our proposed studies are directed towards a better understanding of the role of the C2 domain in the translocation of PTEN and in the regulation of the activity of PTEN via its interaction with other proteins.
|Effective start/end date||9/1/02 → 6/30/07|
- National Institutes of Health: $301,637.00
- National Institutes of Health: $298,795.00
- National Institutes of Health: $299,712.00
- National Institutes of Health: $302,004.00