The lipid phosphatase activity of PTEN is critical for its tumor supressor function

TLDR

Protein tyrosine phosphatases are thought to suppress tumors by antagonizing growth‑promoting kinases, and the PTEN tumor suppressor on chromosome 10q23, whose germ‑line mutations cause Cowden disease and related neoplasias, exemplifies this family. The study aimed to identify PTEN’s physiological substrates to clarify its tumor‑suppressive mechanism. A PTEN missense mutation (G129E) that abolishes its lipid phosphatase activity is linked to Cowden disease, and reintroducing wild‑type or substrate‑trapping PTEN in cells reduces PI3K phospholipid products, inhibits Akt signaling, and restores cell‑survival regulation.

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.