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  • Original Paper
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Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity

Oncogene volume 21, pages 2357–2364 (2002)Cite this article

Abstract

The tumor suppressor gene, MMAC/PTEN, has phosphatase, C2, and PDZ-binding domains as well as potential sites of regulation by phosphorylation, including tyrosine phosphorylation, which may contribute to its ability to modulate cell growth and viability. Several obvious and significant motifs were found in MMAC/PTEN, including most notably, a catalytic domain of tyrosine phosphatase (IHCxxGxxRS/T) and several potential tyrosine phosphorylation sites. To examine the functional significance of tyrosine phosphorylation of MMAC/PTEN, retroviral constructs were generated with mutations at two putative tyrosine phosphorylation sites (Y240A/Y240F and Y315A/Y315F). Stable expression of wild-type MMAC/PTEN in U251 human glioma cells (which do not normally produce a functional MMAC/PTEN gene product) resulted in a significant reduction of tumor growth in nude mice, decreased growth rate, saturation density, and colony formation in vitro, as well as dephosphorylation of D3-phosphorylated phosphatidylinositols (PtdIns) in vitro. Mutation of Y240 or Y315 to either alanine or phenylalanine abrogated the ability of MMAC/PTEN to alter growth rate, saturation density, and colony formation in vitro. The ability of MMAC/PTEN to limit tumor growth in nude mice was markedly decreased but not abrogated by mutation of Y240 or Y315 to alanine. Thus, Y240 and Y315 are required for MMAC/PTEN to decrease tumor growth in vitro and in vivo. In contrast to wild-type MMAC/PTEN, mutant MMAC/PTEN containing Y240A or Y315A was unable to dephosphorylate D3-phosphorylated PtdIns in vitro. Thus, Y240A and Y315A are involved in the ability of MMAC/PTEN to dephosphorylate PtdIns and regulate tumor cell growth in vitro and in vivo.

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Abbreviations

MMAC/PTEN:

mutated in multiple advanced cancers/phosphatase and tensin homologue

PI3K:

phosphatydlinositol 3-Kinase

PtdIns:

phosphatydlinositols

DMEM:

Dulbecco's modified Eagle's medium

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Acknowledgements

This work is dedicated to the memory of the late Dr Peter A Steck. We would like to especially thank Dr Gary E Gallick for invaluable comments and helpful discussion. We also thank Dr Astrid Maria Eder for critical reading of the manuscript. This work was supported by Grants RO1 CA51148 from the National Institute of Health, a grant from the Gilland Foundation to WKA Yung, and Cancer Center Core Grant NCI, CA-16672 and RO1 CA82716 from the National Institutes of Health to GB Mills.

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  1. Department of Neuro-Oncology, Box 100, The Brain Tumor Center, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Dimpy Koul, Samar A Jasser, Michael A Davies, Ruijun Shen, Yuexi Shi & WK Alfred Yung

  2. Department of Molecular Therapeutics, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Yiling Lu & Gordon B Mills

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  1. Dimpy Koul
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Correspondence to WK Alfred Yung.

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Koul, D., Jasser, S., Lu, Y. et al. Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene 21, 2357–2364 (2002). https://doi.org/10.1038/sj.onc.1205296

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