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

  • Hui L
  • Rodrik V
  • Pielak R
 et al. 
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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.

Author-supplied keywords

  • Adaptor Proteins, Signal Transducing
  • Antigens, Polyomavirus Transforming/metabolism
  • Apoptosis
  • Blotting, Western
  • Breast Neoplasms/*pathology
  • Carrier Proteins/metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Humans
  • Immunoprecipitation
  • Models, Biological
  • Mutation
  • Phospholipase D/chemistry/*metabolism
  • Phosphoprotein Phosphatases/*antagonists & inhibit
  • 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

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Authors

  • L Hui

  • V Rodrik

  • R M Pielak

  • S Knirr

  • Y Zheng

  • D A Foster

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