Human Molecular Genetics Advance Access originally published online on April 3, 2007
Human Molecular Genetics 2007 16(10):1157-1163; 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, OH 43210, USA, 2 Genomic Medicine Institute, 3 Lerner Research Institute, 4 Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA, 5 Department of Genetics and 6 CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
* To whom correspondence should be addressed at:, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA. Tel: +1 2164443440; Fax: +1 2166360655; Email: engc{at}ccf.org
Received January 26, 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. As 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 a 51% increase in phosphatidic acid, with a decrease in phosphatidylcholine, suggesting that PTEN may regulate phospholipase D (PLD). PTEN overexpression results in a 30% increase in basal PLD activity. As phospholipase C (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 indicate that the pathogenesis of CS/BRRS has a more complex biochemical basis beyond simply activating the PI3K pathway. This provides alternative routes for PTEN's tumor suppressor action that may be beneficial in the creation of novel targets for cancer therapy and prevention.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.