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The Phosphoinositol Phosphatase Activity of PTEN Mediates a Serum-sensitive G₁ Growth Arrest in Glioma Cells

Ludwig Institute for Cancer Research [F. B. F., H-J. S. H., W. K. C.], Department of Medicine [H-J. S. H., W. K. C.], Center for Molecular Genetics [W. K. C.] and Cancer Center [W. K. C.], University of California-San Diego, La Jolla, California 92093-0660

The PTEN gene (also called MMAC1 and TEP1) at chromosome 10q23 is mutated in a variety of predominantly late-stage tumors and has been shown to suppress glioma cell growth in vitro and in vivo. Here we sought to determine the mechanism by which PTEN mediates growth inhibition. Using the mutant PTEN glioma cell line, U87MG, as a transfection recipient for a series of PTEN alleles, we provide direct evidence that this capacity requires phosphatase activity. Mutations mapping upstream, within, and downstream of the catalytic domain ablated activity toward a 3' phosphorylated phosphoinositide substrate of PTEN, whereas alleles with mutations flanking the catalytic domain retained activity toward the acidic protein polymer substrate, Glu₄Tyr₁. Thus, catalytic activity toward phosphoinositide substrates was required for growth suppression, whereas activity toward the protein substrate was dispensable for growth suppression. Finally, we used apoptotic and cell proliferation analyses to show that PTEN-mediated growth inhibition under reduced serum conditions was due to a G₁ cell cycle block rather than to an induction of apoptosis.

¹ To whom requests for reprints should be addressed, at Ludwig Institute for Cancer Research, San Diego Branch 3080 CMM-East, 9500 Gilman Drive, La Jolla, CA 92093-0660. Phone: (619) 534-7808; Fax: (619) 534-7816; E-mail: ffurnari@ucsd.edu.

Received 8/ 6/98. Accepted 10/ 1/98.

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				X. Shan, M. J. Czar, S. C. Bunnell, P. Liu, Y. Liu, P. L. Schwartzberg, and R. L. Wange Deficiency of PTEN in Jurkat T Cells Causes Constitutive Localization of Itk to the Plasma Membrane and Hyperresponsiveness to CD3 Stimulation Mol. Cell. Biol., September 15, 2000; 20(18): 6945 - 6957. [Abstract] [Full Text]

				F. Vazquez, S. Ramaswamy, N. Nakamura, and W. R. Sellers Phosphorylation of the PTEN Tail Regulates Protein Stability and Function Mol. Cell. Biol., July 15, 2000; 20(14): 5010 - 5018. [Abstract] [Full Text]

				O. Gimm, T. Attie-Bitach, J. A. Lees, M. Vekemans, and C. Eng Expression of the PTEN tumour suppressor protein during human development Hum. Mol. Genet., July 1, 2000; 9(11): 1633 - 1639. [Abstract] [Full Text] [PDF]

				V. Stambolic, M.-S. Tsao, D. Macpherson, A. Suzuki, W. B. Chapman, and T. W. Mak High Incidence of Breast and Endometrial Neoplasia Resembling Human Cowden Syndrome in pten+/- Mice Cancer Res., July 1, 2000; 60(13): 3605 - 3611. [Abstract] [Full Text]

				S.-Y. Han, H. Kato, S. Kato, T. Suzuki, H. Shibata, S. Ishii, K.-i. Shiiba, S. Matsuno, R. Kanamaru, and C. Ishioka Functional Evaluation of PTEN Missense Mutations Using in Vitro Phosphoinositide Phosphatase Assay Cancer Res., June 1, 2000; 60(12): 3147 - 3151. [Abstract] [Full Text]

				L. R.-BORLADO, C. REDONDO, B. ALVAREZ, C. JIMENEZ, L. M. CRIADO, J. FLORES, M. A. R. MARCOS, C. MARTINEZ-A, D. BALOMENOS, and A. C. CARRERA Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo FASEB J, May 1, 2000; 14(7): 895 - 903. [Abstract] [Full Text]

				O. Gimm, A. Perren, L.-P. Weng, D. J. Marsh, J. J. Yeh, U. Ziebold, E. Gil, R. Hinze, L. Delbridge, J. A. Lees, et al. Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors Am. J. Pathol., May 1, 2000; 156(5): 1693 - 1700. [Abstract] [Full Text] [PDF]

				D. Fults and C. Pedone Immunocytochemical mapping of the phosphatase and tensin homolog (PTEN/MMAC1) tumor suppressor protein in human gliomas Neuro-oncol, April 1, 2000; 2(2): 71 - 79. [Abstract] [PDF]

				M. B. Lachyankar, N. Sultana, C. M. Schonhoff, P. Mitra, W. Poluha, S. Lambert, P. J. Quesenberry, N. S. Litofsky, L. D. Recht, R. Nabi, et al. A Role for Nuclear PTEN in Neuronal Differentiation J. Neurosci., February 15, 2000; 20(4): 1404 - 1413. [Abstract] [Full Text] [PDF]

				D. C.I. Goberdhan, N. Paricio, E. C. Goodman, M. Mlodzik, and C. Wilson Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway Genes & Dev., December 15, 1999; 13(24): 3244 - 3258. [Abstract] [Full Text]

				T. Minaguchi, T. Mori, Y. Kanamori, M. Matsushima, H. Yoshikawa, Y. Taketani, and Y. Nakamura Growth Suppression of Human Ovarian Cancer Cells by Adenovirus-mediated Transfer of the PTEN Gene Cancer Res., December 1, 1999; 59(24): 6063 - 6067. [Abstract] [Full Text] [PDF]

				I. U. Ali, L. M. Schriml, and M. Dean Mutational Spectra of PTEN/MMAC1 Gene: a Tumor Suppressor With Lipid Phosphatase Activity J Natl Cancer Inst, November 17, 1999; 91(22): 1922 - 1932. [Abstract] [Full Text] [PDF]

				M. Tamura, J. Gu, H. Tran, and K. M. Yamada PTEN Gene and Integrin Signaling in Cancer J Natl Cancer Inst, November 3, 1999; 91(21): 1820 - 1828. [Abstract] [Full Text] [PDF]

				D. Maier, G. Jones, X. Li, A. H. Schonthal, O. Gratzl, E. G. Van Meir, and A. Merlo The PTEN Lipid Phosphatase Domain Is Not Required to Inhibit Invasion of Glioma Cells Cancer Res., November 1, 1999; 59(21): 5479 - 5482. [Abstract] [Full Text] [PDF]

				L.-P. Weng, W. M. Smith, P. L. M. Dahia, U. Ziebold, E. Gil, J. A. Lees, and C. Eng PTEN Suppresses Breast Cancer Cell Growth by Phosphatase Activity-dependent G1 Arrest followed by Cell Death Cancer Res., November 1, 1999; 59(22): 5808 - 5814. [Abstract] [Full Text] [PDF]

				R. C.T. Aguiar, Y. Yakushijin, S. Kharbanda, S. Tiwari, G. J. Freeman, and M. A. Shipp PTPROt: An Alternatively Spliced and Developmentally Regulated B-Lymphoid Phosphatase That Promotes G0/G1 Arrest Blood, October 1, 1999; 94(7): 2403 - 2413. [Abstract] [Full Text] [PDF]

				M. E. McMenamin, P. Soung, S. Perera, I. Kaplan, M. Loda, and W. R. Sellers Loss of PTEN Expression in Paraffin-embedded Primary Prostate Cancer Correlates with High Gleason Score and Advanced Stage Cancer Res., September 1, 1999; 59(17): 4291 - 4296. [Abstract] [Full Text] [PDF]

				M. Tamura, J. Gu, E. H. J. Danen, T. Takino, S. Miyamoto, and K. M. Yamada PTEN Interactions with Focal Adhesion Kinase and Suppression of the Extracellular Matrix-dependent Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway J. Biol. Chem., July 16, 1999; 274(29): 20693 - 20703. [Abstract] [Full Text] [PDF]

				V. T. Mihaylova, C. Z. Borland, L. Manjarrez, M. J. Stern, and H. Sun The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway PNAS, June 22, 1999; 96(13): 7427 - 7432. [Abstract] [Full Text] [PDF]

				M. A. Davies, D. Koul, H. Dhesi, R. Berman, T. J. McDonnell, D. McConkey, W. K. A. Yung, and P. A. Steck Regulation of Akt/PKB Activity, Cellular Growth, and Apoptosis in Prostate Carcinoma Cells by MMAC/PTEN Cancer Res., June 1, 1999; 59(11): 2551 - 2556. [Abstract] [Full Text] [PDF]

				Y. Tamai, R. Nakajima, T.-o Ishikawa, K. Takaku, M. F. Seldin, and M. M. Taketo Colonic Hamartoma Development by Anomalous Duplication in Cdx2Knockout Mice Cancer Res., June 1, 1999; 59(12): 2965 - 2970. [Abstract] [Full Text] [PDF]

				I. W. Cheney, S. T. C. Neuteboom, M.-T. Vaillancourt, M. Ramachandra, and R. Bookstein Adenovirus-mediated Gene Transfer of MMAC1/PTEN to Glioblastoma Cells Inhibits S Phase Entry by the Recruitment of p27Kip1 into Cyclin E/CDK2 Complexes Cancer Res., May 1, 1999; 59(10): 2318 - 2323. [Abstract] [Full Text] [PDF]