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

Abstract

Since their discovery, protein tyrosine phosphatases have been speculated to play a role in tumor suppression because of their ability to antagonize the growthpromoting 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) B͞Akt and regulation of cell survival.

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

“…We generated ER-targeted chimeras of the PTEN(C124S) mutant, which lacks both lipid and protein phosphatase activities 3 (ER-PTEN(C124S)), and of the PTEN(G129E) mutant, which displays a greatly reduced lipid phosphatase activity while retaining full protein phosphatase activity 31 Figure 4b) were comparable to ER-PTEN for ER-PTEN(G129E), whereas always lower for ER-PTEN(C124S). Consequently, in comparison with ER-PTEN(C124S), ER-PTEN(G129E) retained a greater capability to enhance cell death induced by ArA, as revealed by the higher amount of cytochrome c released into the cytosol (Figure 6d), increased caspase-3 cleavage (Figure 6e) and lower cell viability (Figure 6f) in ER-PTEN(G129E)-overexpressing cells.…”

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

“…25,26 PTEN was mutated or deleted homozygously in glioma, endometrial, and breast carcinoma tumors. [27][28][29] It was reported that PTEN mutations were identified in small cell carcinomas, but not in non-small-cell carcinomas.…”

The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells

“…The effect of PTEN on AKT phosphorylation required the phosphatase activity of PTEN, as no di erences were detected between the e ects of a vector control and those observed using a mutated form of PTEN (PTEN C124S), which ablates both protein and lipid phosphatase activity ( Figure 2B). PTEN lipid phosphatase activity was also critical to the kinetics of AKT phosphorylation as AKT phosphorylation was not altered by a mutated form of PTEN (PTEN G129E) ( Figure 2B) in which phosphatidyinositol 3' phosphatase activity of PTEN is lost, but protein phosphatase activity remains intact (Funari et al, 1998;Myers et al, 1998) (Figure 2B). …”

“…Importantly, PTEN also has the ability to dephosphorylate position D3 of phosphatidylinositol (3,4,5) trisphosphate, the latter of which represents a direct product of phosphatidylinositol 3-kinase (PI3K) activity (Maehama and Dixon, 1998). Strikingly, a number of germline and sporadic mutations in PTEN, such as the substitution of glutamic acid for the glycine residue at position 129 (G129E), ablate the ability of PTEN to dephosphorylate phosphatidylinositol (3,4,5) trisphosphate, but leave PTEN protein phosphatase activity intact (Furnari et al, 1998;Myers et al, 1997Myers et al, , 1998. The association of these mutations with cancer, combined with the capacity of the G129E mutated form of PTEN to dephosphorylate FAK and regulate cell spreading in a fashion indistinguishable from wildtype PTEN (Tamura et al, 1998), indicates that dephosphorylation of phosphatidylinositol (3,4,5) trisphosphate represents a function of PTEN critical to this protein's, ability to act as a tumor suppressor.…”