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[Cancer Research 57, 2124-2129, June 1, 1997]
© 1997 American Association for Cancer Research
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TEP1, Encoded by a Candidate Tumor Suppressor Locus, Is a Novel Protein Tyrosine Phosphatase Regulated by Transforming Growth Factor ß1

Da-Ming Li and Hong Sun2

Department of Genetics. Yale University School of Medicine, New Haven, Connecticut 06520

It has long been postulated that protein tyrosine phosphatases may act as tumor suppressors because of their ability to counteract the oncogenic actions of protein tyrosine kinases. Here we report the cloning and characterization of a novel human protein tyrosine phosphatase, TEP1. TEP1 contains the protein tyrosine phosphatase signature motif, and we show that it possesses an intrinsic protein tyrosine phosphatase activity. TEP1 also shares extensive homology with tensin, a cytoskeletal protein localized to focal adhesions, and with auxilin, a protein involved in synaptic vesicle transport. Immunofluorescence studies show that TEP1 is a cytoplasmic protein. The abundance of TEP1 transcription is altered in many transformed cells. In the transforming growth factor ß-sensitive cells, TEP1 expression is rapidly down-regulated by transforming growth factor ß, a cytokine shown to be involved in regulating cell adhesion and cell motility. We have also mapped the gene encoding TEP1 to chromosome 10q23, a locus that is frequently deleted in a variety of human cancers. TEP1 protein is identical to the protein encoded by the candidate tumor suppressor gene PTEN/MMAC1. Our functional studies of the TEP1 protein suggest that its tumor suppressor function may associate with its intrinsic protein tyrosine phosphatase activity and its cytoplasmic localization.

1 This work was supported in part by the Yale Cancer Research Award and the Pew Charitable Trust. H. S. is a Pew Scholar in the Biomedical Sciences.

2 To whom requests for reprints should be addressed, at Department of Genetics, Yale University School of Medicine, 333 Cedar Street. New Haven. CT 06520. Phone: (203) 737-1923; Fax: (203) 785-7023; E-mail: hong.sun@yale.edu.

Received 4/16/97. Accepted 4/20/97.




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J. Biol. Chem., April 12, 2002; 277(16): 14255 - 14265.
[Abstract] [Full Text] [PDF]

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H. Stocker, M. Andjelkovic, S. Oldham, M. Laffargue, M. P. Wymann, B. A. Hemmings, and E. Hafen
Living with Lethal PIP3 Levels: Viability of Flies Lacking PTEN Restored by a PH Domain Mutation in Akt/PKB
Science, March 15, 2002; 295(5562): 2088 - 2091.
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M. A. Zysman, W. B. Chapman, and B. Bapat
Considerations When Analyzing the Methylation Status of PTEN Tumor Suppressor Gene
Am. J. Pathol., March 1, 2002; 160(3): 795 - 800.
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I. Vancurova, R. Wu, V. Miskolci, and S. Sun
Increased p50/p50 NF-{kappa}B Activation in Human Papillomavirus Type 6- or Type 11-Induced Laryngeal Papilloma Tissue
J. Virol., February 1, 2002; 76(3): 1533 - 1536.
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J. S. Kim, X. Peng, P. K. De, R. L. Geahlen, and D. L. Durden
PTEN controls immunoreceptor (immunoreceptor tyrosine-based activation motif) signaling and the activation of Rac
Blood, January 15, 2002; 99(2): 694 - 697.
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W. Reardon, X.-P. Zhou, and C. Eng
A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association
J. Med. Genet., December 1, 2001; 38(12): 820 - 823.
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G. Dicuonzo, S. Angeletti, J. Garcia-Foncillas, A. Brugarolas, Y. Okrouzhnov, D. Santini, G. Tonini, G. Lorino, M. De Cesaris, and A. Baldi
Colorectal Carcinomas and PTEN/MMAC1 Gene Mutations
Clin. Cancer Res., December 1, 2001; 7(12): 4049 - 4053.
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J. Stolarov, K. Chang, A. Reiner, L. Rodgers, G. J. Hannon, M. H. Wigler, and V. Mittal
Design of a retroviral-mediated ecdysone-inducible system and its application to the expression profiling of the PTEN tumor suppressor
PNAS, October 25, 2001; (2001) 221450598.
[Abstract] [Full Text] [PDF]

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H. Huang, J. C. Cheville, Y. Pan, P. C. Roche, L. J. Schmidt, and D. J. Tindall
PTEN Induces Chemosensitivity in PTEN-mutated Prostate Cancer Cells by Suppression of Bcl-2 Expression
J. Biol. Chem., October 12, 2001; 276(42): 38830 - 38836.
[Abstract] [Full Text] [PDF]

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T. Liu, J. Chen, S. Salahshor, S. Kuismanen, E. Holmberg, H. Gronberg, P. Peltomaki, and A. Lindblom
Screening families with endometrial and colorectal cancers for germline mutations
J. Med. Genet., September 1, 2001; 38(9): e29 - 29.
[Full Text] [PDF]

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G. B. Mills, Y. Lu, and E. C. Kohn
Linking molecular therapeutics to molecular diagnostics: Inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo
PNAS, August 28, 2001; 98(18): 10031 - 10033.
[Full Text] [PDF]

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 NeuroscientistHome page
A. H. Ross, M. B. Lachyankar, and L. D. Recht
PTEN: A Newly Identified Regulator of Neuronal Differentiation
Neuroscientist, August 1, 2001; 7(4): 278 - 281.
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H. Ono, H. Katagiri, M. Funaki, M. Anai, K. Inukai, Y. Fukushima, H. Sakoda, T. Ogihara, Y. Onishi, M. Fujishiro, et al.
Regulation of Phosphoinositide Metabolism, Akt Phosphorylation, and Glucose Transport by PTEN (Phosphatase and Tensin Homolog Deleted on Chromosome 10) in 3T3-L1 Adipocytes
Mol. Endocrinol., August 1, 2001; 15(8): 1411 - 1422.
[Abstract] [Full Text] [PDF]

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C. M. van Golen, T. S. Schwab, K. M. W. Ignatoski, S. P. Ethier, and E. L. Feldman
PTEN/MMAC1 Overexpression Decreases Insulin-like Growth Factor-I-mediated Protection from Apoptosis in Neuroblastoma Cells
Cell Growth Differ., July 1, 2001; 12(7): 371 - 378.
[Abstract] [Full Text] [PDF]

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T. Tolkacheva, M. Boddapati, A. Sanfiz, K. Tsuchida, A. C. Kimmelman, and A. M-L. Chan
Regulation of PTEN Binding to MAGI-2 by Two Putative Phosphorylation Sites at Threonine 382 and 383
Cancer Res., July 1, 2001; 61(13): 4985 - 4989.
[Abstract] [Full Text] [PDF]

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H. Sasaki, M. C. Zlatescu, R. A. Betensky, Y. Ino, J. G. Cairncross, and D. N. Louis
PTEN Is a Target of Chromosome 10q Loss in Anaplastic Oligodendrogliomas and PTEN Alterations Are Associated with Poor Prognosis
Am. J. Pathol., July 1, 2001; 159(1): 359 - 367.
[Abstract] [Full Text] [PDF]

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K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng
Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas
Am. J. Pathol., June 1, 2001; 158(6): 2097 - 2106.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J.-i. Hisatake, J. O'Kelly, M. R. Uskokovic, S. Tomoyasu, and H. P. Koeffler
Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells
Blood, April 15, 2001; 97(8): 2427 - 2433.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
L.-P. Weng, J. L. Brown, and C. Eng
PTEN coordinates G1 arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model
Hum. Mol. Genet., March 1, 2001; 10(6): 599 - 604.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
L.-P. Weng, W. M. Smith, J. L. Brown, and C. Eng
PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model
Hum. Mol. Genet., March 1, 2001; 10(6): 605 - 616.
[Abstract] [Full Text] [PDF]

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L.-P. Weng, J. L. Brown, and C. Eng
PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways
Hum. Mol. Genet., February 1, 2001; 10(3): 237 - 242.
[Abstract] [Full Text] [PDF]

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L.-P. Weng, O. Gimm, J. B. Kum, W. M. Smith, X.-P. Zhou, D. Wynford-Thomas, G. Leone, and C. Eng
Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death
Hum. Mol. Genet., February 1, 2001; 10(3): 251 - 258.
[Abstract] [Full Text] [PDF]

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J.-T. Dong, C.-L. Li, T. W. Sipe, and H. F. Frierson Jr.
Mutations of PTEN/MMAC1 in Primary Prostate Cancers from Chinese Patients
Clin. Cancer Res., February 1, 2001; 7(2): 304 - 308.
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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.
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N. Nakamura, S. Ramaswamy, F. Vazquez, S. Signoretti, M. Loda, and W. R. Sellers
Forkhead Transcription Factors Are Critical Effectors of Cell Death and Cell Cycle Arrest Downstream of PTEN
Mol. Cell. Biol., December 1, 2000; 20(23): 8969 - 8982.
[Abstract] [Full Text]

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 Proc. Natl. Acad. Sci. USAHome page
J. Heymont, L. Berenfeld, J. Collins, A. Kaganovich, B. Maynes, A. Moulin, I. Ratskovskaya, P. P. Poon, G. C. Johnston, M. Kamenetsky, et al.
TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation
PNAS, November 7, 2000; 97(23): 12672 - 12677.
[Abstract] [Full Text] [PDF]

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C. Eng
Will the real Cowden syndrome please stand up: revised diagnostic criteria
J. Med. Genet., November 1, 2000; 37(11): 828 - 830.
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X.-P. Zhou, O. Gimm, H. Hampel, T. Niemann, M. J. Walker, and C. Eng
Epigenetic PTEN Silencing in Malignant Melanomas without PTEN Mutation
Am. J. Pathol., October 1, 2000; 157(4): 1123 - 1128.
[Abstract] [Full Text] [PDF]

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T.-M. Hong, P.-C. Yang, K. Peck, J. J. W. Chen, S.-C. Yang, Y.-C. Chen, and C.-W. Wu
Profiling the Downstream Genes of Tumor Suppressor PTEN in Lung Cancer Cells by Complementary DNA Microarray
Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 355 - 363.
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J. T. Çelebi, I. Shendrik, D. N Silvers, and M. Peacocke
Identification of PTEN mutations in metastatic melanoma specimens
J. Med. Genet., September 1, 2000; 37(9): 653 - 657.
[Abstract] [Full Text]

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A.-M. Martin and B. L. Weber
Genetic and Hormonal Risk Factors in Breast Cancer
J Natl Cancer Inst, July 19, 2000; 92(14): 1126 - 1135.
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 Mol. Cell. Biol.Home page
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.
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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.
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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.
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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.
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I. De Vivo, D. M Gertig, S. Nagase, S. E Hankinson, R. O'Brien, F. E Speizer, R. Parsons, and D. J Hunter
Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers
J. Med. Genet., May 1, 2000; 37(5): 336 - 341.
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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]


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