Human Molecular Genetics Advance Access published online on April 3, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm063
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PTEN Regulates Phospholipase D and Phospholipase C
1 Department of Evolution, Ecology and Organismal Biology, The Ohio State University, Columbus, Ohio 43210, USA 2 Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA 3 Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA 4 Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA 5 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA 6 CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
* Corresponding Author Charis Eng, MD, PhD, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, Tel: +1 216 444 3440, Fax: +1 216 636 0655, email: engc{at}ccf.org
Received January 26, 2007; Revised March 13, 2007; Accepted March 13, 2007
PTEN is an ubiquitously expressed tumor suppressor which plays a prominent role in the pathogenesis of many types of sporadic solid tumors, including breast cancer, as well as hematologic malignancies. Germline PTEN mutations cause 85% of Cowden syndrome (CS), characterized by a high risk of breast and thyroid cancers, and 65% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), characterized by lipomatosis, hemangiomas and speckled penis. Historically, PTEN's role in tumor suppression has been linked to the down-regulation of the PI3K/AKT pathway by PTEN's lipid phosphatase activity. Beyond the AKT pathway, however, there has been minimal examination of PTEN's responsibility in lipid-derived cellular signaling. Since phospholipids have been shown to be critical components in signal transduction and cellular proliferation and PTEN controls cellular phospholipid levels, we hypothesized that PTEN functions as a regulator of lipid signaling and homeostasis. Increased PTEN expression in unstimulated MCF-7 breast cancer cells results in 51% increase in phosphatidic acid with a decrease in phosphatidylcholine, suggesting that PTEN may regulate PLD. PTEN overexpression results in 30% increase in basal PLD activity. Since PLC is both involved in PLD activation and is regulated by PIP2/3 levels, we investigated the role of PTEN on PLC activation. Our data suggest that PTEN modulates PLC:PLD activation pathways and indicates that the pathogenesis of CS/BRRS has a more complex biochemical basis beyond simply activating the PI3K pathway. This provides alternative routes of action for PTEN's tumor suppressor action that may be beneficial in the creation of novel targets for cancer therapy and prevention.
Contributed equally to this work and should be considered joint first authors