mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells.

Abstract

A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin (mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells.

• Authors: Li Hui, Vanessa Rodrik, Rafal M Pielak, Stefan Knirr, Yang Zheng, David A Foster
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 43 Pg. 35829-35 (Oct 28 2005) ISSN: 0021-9258 [Print] United States
• PMID: 16109716 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antigens, Polyomavirus Transforming
• Carrier Proteins
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Phosphoproteins
• RNA, Small Interfering
• Serine
• Protein Kinases
• MTOR protein, human
• Ribosomal Protein S6 Kinases
• TOR Serine-Threonine Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 2
• Phospholipase D

Topics

• Adaptor Proteins, Signal Transducing
• Antigens, Polyomavirus Transforming (metabolism)
• Apoptosis
• Blotting, Western
• Breast Neoplasms (pathology)
• Carrier Proteins (metabolism)
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Survival
• Humans
• Immunoprecipitation
• Models, Biological
• Mutation
• Phospholipase D (chemistry, metabolism)
• Phosphoprotein Phosphatases (antagonists & inhibitors)
• Phosphoproteins (metabolism)
• Phosphorylation
• Protein Kinases (metabolism, physiology)
• Protein Phosphatase 2
• RNA, Small Interfering (metabolism)
• Ribosomal Protein S6 Kinases (metabolism)
• Ribosomes (enzymology)
• Serine (chemistry)
• TOR Serine-Threonine Kinases