The Lipid Phosphatase Activity of PTEN is Critical for Its Tumor Supressor Function

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-11, Vol.95 (23), p.13513-13518
Main Authors: Myers, Michael P., Pass, Ian, Batty, Ian H., Van Der Kaay, Jeroen, Stolarov, Javor P., Hemmings, Brian A., Wigler, Michael H., Downes, C. Peter, Tonks, Nicholas K.
Format: Article
Language:English
Subjects:
Biological Sciences
Cell Line
Cell lines
Disease
Escherichia coli
Genes, Tumor Suppressor
Germ-Line Mutation
Glioblastoma
HEK293 cells
Humans
Lipids
Memory interference
Multiple hamartoma syndrome
Phosphatases
Phosphates
Phosphatidylinositols
Phosphoric Monoester Hydrolases - chemistry
Phosphoric Monoester Hydrolases - genetics
Phosphoric Monoester Hydrolases - metabolism
Protein Tyrosine Phosphatases
Proteins
PTEN Phosphohydrolase
Tumor cell line
Tumor Suppressor Proteins
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.23.13513