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The lipid phosphatase activity of PTEN is critical for its tumor supressor function
1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724-2208, USA.
Abstract:
Since their discovery, protein tyrosine phosphatases have been speculated to play a role in tumor suppression because of their ability to antagonize the growth-promoting protein tyrosine kinases. Recently, a tumor suppressor from human chromosome 10q23, called PTEN or MMAC1, has been identified that shares homology with the protein tyrosine phosphatase family. Germ-line mutations in PTEN give rise to several related neoplastic disorders, including Cowden disease. A key step in understanding the function of PTEN as a tumor suppressor is to identify its physiological substrates. Here we report that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease. Furthermore, expression of wild-type or substrate-trapping forms of PTEN in HEK293 cells altered the levels of the phospholipid products of phosphatidylinositol 3-kinase and ectopic expression of the phosphatase in PTEN-deficient tumor cell lines resulted in the inhibition of protein kinase (PK) B/Akt and regulation of cell survival.
Insights
Protein tyrosine phosphatase PTEN
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein tyrosine phosphatases (PTPs) antagonize protein tyrosine kinases, suggesting a tumor suppressor role.
- PTEN (also known as MMAC1) is a human tumor suppressor gene located on chromosome 10q23.
- Germline mutations in PTEN are linked to neoplastic disorders like Cowden disease.
Purpose of the Study:
- To identify the physiological substrates of PTEN to understand its tumor suppressor function.
- To investigate the role of PTEN's lipid phosphatase activity in Cowden disease etiology.
- To explore PTEN's effects on phosphatidylinositol 3-kinase signaling and cell survival.
Main Methods:
- Characterization of a PTEN-G129E missense mutation found in Cowden disease patients.
- Expression of wild-type and mutant PTEN in HEK293 cells.
- Analysis of phospholipid products of phosphatidylinositol 3-kinase.
- Ectopic expression of PTEN in PTEN-deficient tumor cell lines.
Main Results:
- The PTEN-G129E mutation specifically abolishes PTEN's recognition of inositol phospholipids, implicating lipid phosphatase activity in disease.
- PTEN expression altered phosphatidylinositol 3-kinase pathway phospholipid products.
- Ectopic PTEN expression inhibited protein kinase B/Akt and regulated cell survival in tumor cells.
Conclusions:
- Loss of PTEN's lipid phosphatase activity is likely responsible for Cowden disease.
- PTEN plays a crucial role in regulating phosphatidylinositol 3-kinase signaling and cell survival.
- Understanding PTEN's substrate specificity is key to its function as a tumor suppressor.