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 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.

[1]  L. Cantley,et al.  Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. , 1997, Science.

[2]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[3]  R. Kobayashi,et al.  Serine Phosphorylation-dependent Association of the Band 4.1-related Protein-tyrosine Phosphatase PTPH1 with 14-3-3β Protein* , 1997, The Journal of Biological Chemistry.

[4]  P. Cohen,et al.  Role of Translocation in the Activation and Function of Protein Kinase B* , 1997, The Journal of Biological Chemistry.

[5]  N. Tonks,et al.  Identification of p130(cas) as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST , 1996, Molecular and cellular biology.

[6]  N. Tonks,et al.  Epidermal Growth Factor Receptor and the Adaptor Protein p52Shc Are Specific Substrates of T-Cell Protein Tyrosine Phosphatase , 1998, Molecular and Cellular Biology.

[7]  J Downward,et al.  PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. , 1997, Trends in biochemical sciences.

[8]  J. Bruce,et al.  Somatic mutations of PTEN in glioblastoma multiforme. , 1997, Cancer research.

[9]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[10]  Kathleen R. Cho,et al.  Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. , 1997, Cancer research.

[11]  M. Wigler,et al.  P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  L. Rohrschneider,et al.  p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. , 1996, Genes & development.

[13]  I. Batty,et al.  A Novel, Rapid, and Highly Sensitive Mass Assay for Phosphatidylinositol 3,4,5-Trisphosphate (PtdIns(3,4,5)P3) and Its Application to Measure Insulin-stimulated PtdIns(3,4,5)P3 Production in Rat Skeletal Muscle in Vivo* , 1997, The Journal of Biological Chemistry.

[14]  S. Seal,et al.  Cowden syndrome and Lhermitte-Duclos disease in a family: a single genetic syndrome with pleiotropy? , 1994, Journal of medical genetics.

[15]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[16]  G. Cooper,et al.  Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway* , 1998, The Journal of Biological Chemistry.

[17]  A. Toker,et al.  Signalling through the lipid products of phosphoinositide-3-OH kinase , 1997, Nature.

[18]  H. Land,et al.  Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. , 1990, Nucleic acids research.

[19]  P. Cohen,et al.  Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα , 1997, Current Biology.

[20]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[21]  R. Vessella,et al.  Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Myers,et al.  PTEN: sometimes taking it off can be better than putting it on. , 1997, American journal of human genetics.

[23]  R. McLendon,et al.  PTEN gene mutations are seen in high-grade but not in low-grade gliomas. , 1997, Cancer research.

[24]  Jing Li,et al.  Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome , 1997, Nature Genetics.

[25]  J. Bos.  A target for phosphoinositide 3-kinase: Akt/PKB. , 1995, Trends in biochemical sciences.

[26]  J. Herman,et al.  Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. , 1997, Cancer research.

[27]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[28]  Carlos Cordon-Cardo,et al.  Pten is essential for embryonic development and tumour suppression , 1998, Nature Genetics.

[29]  J. Testa,et al.  A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. , 1991, Science.

[30]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[31]  A. Berchuck,et al.  PTEN/MMAC1 mutations in endometrial cancers. , 1997, Cancer research.