scholarly journals mTOR-dependent Suppression of Protein Phosphatase 2A Is Critical for Phospholipase D Survival Signals in Human Breast Cancer Cells

2005 ◽  
Vol 280 (43) ◽  
pp. 35829-35835 ◽  
Author(s):  
Li Hui ◽  
Vanessa Rodrik ◽  
Rafal M. Pielak ◽  
Stefan Knirr ◽  
Yang Zheng ◽  
...  
Keyword(s):  
Phospholipase D ◽  
Protein Phosphatase ◽  
Human Breast Cancer ◽  
Protein Phosphatase 2A ◽  
T Antigen ◽  
Human Breast ◽  
Phosphatase 2A ◽  
Small T Antigen ◽  
Sv40 Small T ◽  
Survival Signals

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.

Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A

Cell ◽  
1990 ◽  
Vol 60 (1) ◽  
pp. 167-176 ◽  
Author(s):  
David C. Pallas ◽  
Lilian K. Shahrik ◽  
Bruce L. Martin ◽  
Stephen Jaspers ◽  
Thomas B. Miller ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
T Antigen ◽  
T Antigens ◽  
Phosphatase 2A ◽  
Small T Antigen ◽  
Sv40 Small T

Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen

1991 ◽  
Vol 11 (4) ◽  
pp. 1996-2003 ◽  
Author(s):  
K H Scheidtmann ◽  
M C Mumby ◽  
K Rundell ◽  
G Walter
Keyword(s):  
Protein Phosphatase ◽  
P53 Protein ◽  
Protein Phosphatase 2A ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Large T Antigen ◽  
C Subunit ◽  
Phosphatase 2A ◽  
Small T Antigen

Simian virus 40 (SV40) large-T antigen and the cellular protein p53 were phosphorylated in vivo by growing cells in the presence of 32Pi. The large-T/p53 complex was isolated by immunoprecipitation and used as a substrate for protein phosphatase 2A (PP2A) consisting of the catalytic subunit (C) and the two regulatory subunits, A and B. Three different purified forms of PP2A, including free C, the AC form, and the ABC form, could readily dephosphorylate both proteins. With both large-T and p53, the C subunit was most active, followed by the AC form, which was more active than the ABC form. The activity of all three forms of PP2A toward these proteins was strongly stimulated by manganese ions and to a lesser extent by magnesium ions. The presence of complexed p53 did not affect the dephosphorylation of large-T antigen by PP2A. The dephosphorylation of individual phosphorylation sites of large-T and p53 were determined by two-dimensional peptide mapping. Individual sites within large-T and p53 were dephosphorylated at different rates by all three forms of PP2A. The phosphates at Ser-120 and Ser-123 of large-T, which affect binding to the origin of SV40 DNA, were removed most rapidly. Three of the six major phosphopeptides of p53 were readily dephosphorylated, while the remaining three were relatively resistant to PP2A. Dephosphorylation of most of the sites in large-T and p53 by the AC form was inhibited by SV40 small-t antigen. The inhibition was most apparent for those sites which were preferentially dephosphorylated. Inhibition was specific for the AC form; no effect was observed on the dephosphorylation of either protein by the free C subunit or the ABC form. The inhibitory effect of small-t on dephosphorylation by PP2A could explain its role in transformation.

Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40

2007 ◽  
Vol 14 (6) ◽  
pp. 527-534 ◽  
Author(s):  
Yu Chen ◽  
Yanhui Xu ◽  
Qing Bao ◽  
Yongna Xing ◽  
Zhu Li ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
T Antigen ◽  
Phosphatase 2A ◽  
Small T Antigen

scholarly journals Dephosphorylation of JC virus agnoprotein by protein phosphatase 2A: Inhibition by small t antigen

Virology ◽  
2008 ◽  
Vol 375 (2) ◽  
pp. 464-479 ◽  
Author(s):  
Ilker K. Sariyer ◽  
Kamel Khalili ◽  
Mahmut Safak
Keyword(s):  
Protein Phosphatase ◽  
Jc Virus ◽  
Protein Phosphatase 2A ◽  
T Antigen ◽  
Phosphatase 2A ◽  
Small T Antigen

scholarly journals Simian Virus 40 Small t Antigen Mediates Conformation-Dependent Transfer of Protein Phosphatase 2A onto the Androgen Receptor

2005 ◽  
Vol 25 (4) ◽  
pp. 1298-1308 ◽  
Author(s):  
Chun-Song Yang ◽  
Michael J. Vitto ◽  
Scott A. Busby ◽  
Benjamin A. Garcia ◽  
Cristina T. Kesler ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Protein Phosphatase ◽  
Tumor Antigens ◽  
Protein Phosphatase 2A ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Phosphatase 2A ◽  
A Subunit ◽  
Small T Antigen

ABSTRACT The tumor antigens simian virus 40 small t antigen (ST) and polyomavirus small and medium T antigens mediate cell transformation in part by binding to the structural A subunit of protein phosphatase 2A (PP2A). The replacement of B subunits by tumor antigens inhibits PP2A activity and prolongs phosphorylation-dependent signaling. Here we show that ST mediates PP2A A/C heterodimer transfer onto the ligand-activated androgen receptor (AR). Transfer by ST is strictly dependent on the agonist-activated conformation of AR, occurs within minutes of the addition of androgen to cells, and can occur in either the cytoplasm or the nucleus. The binding of ST changes the conformation of the A subunit, and ST rapidly dissociates from the complex upon PP2A A/C heterodimer binding to AR. PP2A is transferred onto the carboxyl-terminal half of AR, and the phosphatase activity is directed to five phosphoserines in the amino-terminal activation function region 1, with a corresponding reduction in transactivation. Thus, ST functions as a transfer factor to specify PP2A targeting in the cell and modulates the transcriptional activity of AR.

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