This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Georgescu, M.-M. Articles by Hanafusa, H. Search for Related Content PubMed PubMed Citation Articles by Georgescu, M.-M. Articles by Hanafusa, H.

Stabilization and Productive Positioning Roles of the C2 Domain of PTEN Tumor Suppressor

Laboratory of Molecular Oncology, The Rockefeller University, New York, New York 10021 [M-M. G., K. H. K., H. H.]; Department of Medicine [P. K.] and Cellular Biochemistry and Biophysics Program [H. Y., N. P. P.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Osaka Bioscience Institute, Osaka 565-0874, Japan [H. H.]

PTEN is a tumor suppressor frequently inactivated in brain, prostate, and uterine cancer. It acts as a phosphoinositide phosphatase and consists of an amino-terminal phosphatase domain tightly linked to a COOH-terminal C2 domain involved in lipid membrane-binding. We investigated the functions of the C2 domain and their relevance for tumor growth. To discriminate between PTEN C2 domain ability to recruit or to position the active site to the membrane, we artificially membrane-targeted PTEN by a myristoylation signal. This modification increased wild-type PTEN growth inhibition but did not rescue a C2 mutant defective in lipid-binding, suggesting a model in which PTEN C2 domain positions the active site productively with respect to the membrane-bound phosphoinositide substrate. When tumor-derived mutations in the loops that connect the C2 ß-strands were analyzed, we found that these generally destabilized the protein but had variable effects on the phosphatase activity and tumor growth. The magnitude of these effects was dependent on the presence of the COOH-terminal PEST sequences and on the cell type where the mutant proteins were expressed, suggesting the existence of fluctuating structural defects of the mutant protein. One of the C2 loop mutants induced a total loss of PTEN tumor-suppressor function, most likely by affecting both the membrane binding and the protein stability. These data support a double role for PTEN C2 domain in protein stability and in productive orientation of the catalytic site.

This article has been cited by other articles:

				A. K. Lucio-Eterovic, Y. Piao, and J. F. de Groot Mediators of Glioblastoma Resistance and Invasion during Antivascular Endothelial Growth Factor Therapy Clin. Cancer Res., July 15, 2009; 15(14): 4589 - 4599. [Abstract] [Full Text] [PDF]

				M. Rahdar, T. Inoue, T. Meyer, J. Zhang, F. Vazquez, and P. N. Devreotes A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN PNAS, January 13, 2009; 106(2): 480 - 485. [Abstract] [Full Text] [PDF]

				J. W. Kim, K. H. Kang, P. Burrola, T. W. Mak, and G. Lemke Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium Genes & Dev., November 15, 2008; 22(22): 3147 - 3157. [Abstract] [Full Text] [PDF]

				T. Ikenoue, K. Inoki, B. Zhao, and K.-L. Guan PTEN Acetylation Modulates Its Interaction with PDZ Domain Cancer Res., September 1, 2008; 68(17): 6908 - 6912. [Abstract] [Full Text] [PDF]

				C. Canetti, C. H. Serezani, R. G. Atrasz, E. S. White, D. M. Aronoff, and M. Peters-Golden Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of Fc{gamma}R Phagocytosis by Prostaglandin E2 in Alveolar Macrophages J. Immunol., December 15, 2007; 179(12): 8350 - 8356. [Abstract] [Full Text] [PDF]

				Y. G. Langdon, S. C. Goetz, A. E. Berg, J. T. Swanik, and F. L. Conlon SHP-2 is required for the maintenance of cardiac progenitors Development, November 15, 2007; 134(22): 4119 - 4130. [Abstract] [Full Text] [PDF]

				L. Odriozola, G. Singh, T. Hoang, and A. M. Chan Regulation of PTEN Activity by Its Carboxyl-terminal Autoinhibitory Domain J. Biol. Chem., August 10, 2007; 282(32): 23306 - 23315. [Abstract] [Full Text] [PDF]

				F. C. Morales, Y. Takahashi, S. Momin, H. Adams, X. Chen, and M.-M. Georgescu NHERF1/EBP50 Head-to-Tail Intramolecular Interaction Masks Association with PDZ Domain Ligands Mol. Cell. Biol., April 1, 2007; 27(7): 2527 - 2537. [Abstract] [Full Text] [PDF]

				Y. Tang and C. Eng p53 Down-Regulates Phosphatase and Tensin Homologue Deleted on Chromosome 10 Protein Stability Partially through Caspase-Mediated Degradation in Cells with Proteasome Dysfunction. Cancer Res., June 15, 2006; 66(12): 6139 - 6148. [Abstract] [Full Text] [PDF]

				D. M. Flaherty, M. M. Monick, and S. L. Hinde Human Alveolar Macrophages Are Deficient in PTEN: THE ROLE OF ENDOGENOUS OXIDANTS J. Biol. Chem., February 24, 2006; 281(8): 5058 - 5064. [Abstract] [Full Text] [PDF]

				E. B. Dickerson, R. Thomas, S. P. Fosmire, A. R. Lamerato-Kozicki, S. R. Bianco, J. W. Wojcieszyn, M. Breen, S. C. Helfand, and J. F. Modiano Mutations of Phosphatase and Tensin Homolog Deleted from Chromosome 10 in Canine Hemangiosarcoma Vet. Pathol., September 1, 2005; 42(5): 618 - 632. [Abstract] [Full Text] [PDF]

				J.-H. Chung, M. E. Ginn-Pease, and C. Eng Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal-Like Sequences for Nuclear Import Mediated by Major Vault Protein Cancer Res., May 15, 2005; 65(10): 4108 - 4116. [Abstract] [Full Text] [PDF]

				E. S. White, R. G. Atrasz, E. G. Dickie, D. M. Aronoff, V. Stambolic, T. W. Mak, B. B. Moore, and M. Peters-Golden Prostaglandin E2 Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor-Mediated Increase in PTEN Activity Am. J. Respir. Cell Mol. Biol., February 1, 2005; 32(2): 135 - 141. [Abstract] [Full Text] [PDF]

				M. E. K. Olsten, D. A. Canton, C. Zhang, P. A. Walton, and D. W. Litchfield The Pleckstrin Homology Domain of CK2 Interacting Protein-1 Is Required for Interactions and Recruitment of Protein Kinase CK2 to the Plasma Membrane J. Biol. Chem., October 1, 2004; 279(40): 42114 - 42127. [Abstract] [Full Text] [PDF]

				H. Huang, D. C. Muddiman, and D. J. Tindall Androgens Negatively Regulate Forkhead Transcription Factor FKHR (FOXO1) through a Proteolytic Mechanism in Prostate Cancer Cells J. Biol. Chem., April 2, 2004; 279(14): 13866 - 13877. [Abstract] [Full Text] [PDF]

				E. A. Orchiston, D. Bennett, N. R. Leslie, R. G. Clarke, L. Winward, C. P. Downes, and S. T. Safrany PTEN M-CBR3, a Versatile and Selective Regulator of Inositol 1,3,4,5,6-Pentakisphosphate (Ins(1,3,4,5,6)P5): EVIDENCE FOR Ins(1,3,4,5,6)P5 AS A PROLIFERATIVE SIGNAL J. Biol. Chem., January 9, 2004; 279(2): 1116 - 1122. [Abstract] [Full Text] [PDF]

				D. C.I. Goberdhan and C. Wilson PTEN: tumour suppressor, multifunctional growth regulator and more Hum. Mol. Genet., October 15, 2003; 12(90002): R239 - 248. [Abstract] [Full Text] [PDF]

				Y. Lu, Q. Yu, J. H. Liu, J. Zhang, H. Wang, D. Koul, J. S. McMurray, X. Fang, W.K. A. Yung, K. A. Siminovitch, et al. Src Family Protein-tyrosine Kinases Alter the Function of PTEN to Regulate Phosphatidylinositol 3-Kinase/AKT Cascades J. Biol. Chem., October 10, 2003; 278(41): 40057 - 40066. [Abstract] [Full Text] [PDF]

				A. Radu, V. Neubauer, T. Akagi, H. Hanafusa, and M.-M. Georgescu PTEN Induces Cell Cycle Arrest by Decreasing the Level and Nuclear Localization of Cyclin D1 Mol. Cell. Biol., September 1, 2003; 23(17): 6139 - 6149. [Abstract] [Full Text] [PDF]

				S. Das, J. E. Dixon, and W. Cho Membrane-binding and activation mechanism of PTEN PNAS, June 24, 2003; 100(13): 7491 - 7496. [Abstract] [Full Text] [PDF]

				J M Smith, E P E Kirk, G Theodosopoulos, G M Marshall, J Walker, M Rogers, M Field, J J Brereton, and D J Marsh Germline mutation of the tumour suppressor PTEN in Proteus syndrome J. Med. Genet., December 1, 2002; 39(12): 937 - 940. [Full Text] [PDF]

				C. B. Knobbe, A. Merlo, and G. Reifenberger Pten signaling in gliomas Neuro-oncol, July 1, 2002; 4(3): 196 - 211. [Abstract] [PDF]

				Z. Xu, D. Stokoe, L. P. Kane, and A. Weiss The Inducible Expression of the Tumor Suppressor Gene PTEN Promotes Apoptosis and Decreases Cell Size by Inhibiting the PI3K/Akt Pathway in Jurkat T Cells Cell Growth Differ., July 1, 2002; 13(7): 285 - 296. [Abstract] [Full Text]

				K. M. Yamada and M. Araki Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis J. Cell Sci., January 7, 2001; 114(13): 2375 - 2382. [Abstract] [Full Text] [PDF]

				F. Vazquez, S. R. Grossman, Y. Takahashi, M. V. Rokas, N. Nakamura, and W. R. Sellers Phosphorylation of the PTEN Tail Acts as an Inhibitory Switch by Preventing Its Recruitment into a Protein Complex J. Biol. Chem., December 21, 2001; 276(52): 48627 - 48630. [Abstract] [Full Text] [PDF]