mTOR-dependent suppression of protein phosphatase 2A is critical for phospholipase D survival signals in human breast cancer cells.
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.
Hui
Li
L
Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10021, USA.
Rodrik
Vanessa
V
Pielak
Rafal M
RM
Knirr
Stefan
S
Zheng
Yang
Y
Foster
David A
DA
D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D009154:Mutation; D010739:Phospholipase D / Q000737:chemistry / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D054648:Protein Phosphatase 2; D034741:RNA, Small Interfering / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012270:Ribosomes / Q000201:enzymology; D012694:Serine / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D012694:Serine; D011494:Protein Kinases; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D010739:Phospholipase D