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The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin-linked kinase activity

Oncogene volume 19, pages 200–209 (2000)Cite this article

Abstract

Loss of the tumor suppressor MMAC1 has been shown to be involved in breast, prostate and brain cancer. Consistent with its identification as a tumor suppressor, expression of MMAC1 has been demonstrated to reduce cell proliferation, tumorigenicity, and motility as well as affect cell–cell and cell–matrix interactions of malignant human glioma cells. Subsequently, MMAC1 was shown to have lipid phosphatase activity towards PIP3 and protein phosphatase activity against focal adhesion kinase (FAK). The lipid phosphatase activity of MMAC1 results in decreased activation of the PIP3-dependent, anti-apoptotic kinase, AKT. It is thought that this inhibition of AKT culminates with reduced glioma cell proliferation. In contrast, MMAC1's effects on cell motility, cell–cell and cell–matrix interactions are thought to be due to its protein phosphatase activity towards FAK. However, recent studies suggest that the lipid phosphatase activity of MMAC1 correlates with its ability to be a tumor suppressor. The high rate of mutation of MMAC1 in late stage metastatic tumors suggests that effects of MMAC1 on motility, cell–cell and cell–matrix interactions are due to its tumor suppressor activity. Therefore the lipid phosphatase activity of MMAC1 may affect PIP3 dependent signaling pathways and result in reduced motility and altered cell–cell and cell–matrix interactions. We demonstrate here that expression of MMAC1 in human glioma cells reduced intracellular levels of inositol trisphosphate and inhibited extracellular Ca2+ influx, suggesting that MMAC1 affects the phospholipase C signaling pathway. In addition, we show that MMAC1 expression inhibits integrin-linked kinase activity. Furthermore, we show that these effects require the catalytic activity of MMAC1. Our data thus provide a link of MMAC1 to PIP3 dependent signaling pathways that regulate cell–matrix and cell–cell interactions as well as motility. Lastly, we demonstrate that AKT3, an isoform of AKT highly expressed in the brain, is also a target for MMAC1 repression. These data suggest an important role for AKT3 in glioblastoma multiforme. We therefore propose that repression of multiple PIP3 dependent signaling pathways may be required for MMAC1 to act as a tumor suppressor.

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Acknowledgements

We are grateful to Madeline Fort for providing mouse tissues and thank the FACS facility for help with the calcium flux assays. We also thank Emma Lees and Jing Wang for helpful comments on the manuscript and Maribel Andonian and Gary Burget for graphics support. DNAX Research Institute is fully supported by Schering-Plough Corporation.

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Authors and Affiliations

  1. Department of Cell Signaling, DNAX Research Institute, 901 California Ave, Palo Alto, 94304, California, CA, USA

    Alyssa M Morimoto, Michael G Tomlinson & Ronald Herbst

  2. Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, 94305, California, CA, USA

    Kaname Nakatani & Richard A Roth

  3. Department of Oncology, Hoechst Marion Roussel, Bridgewater, 08807, New Jersey, NJ, USA

    Joseph B Bolen

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  1. Alyssa M Morimoto
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  2. Michael G Tomlinson
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  4. Joseph B Bolen
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Morimoto, A., Tomlinson, M., Nakatani, K. et al. The MMAC1 tumor suppressor phosphatase inhibits phospholipase C and integrin-linked kinase activity. Oncogene 19, 200–209 (2000). https://doi.org/10.1038/sj.onc.1203288

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