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Protein phosphatase 2A is a critical regulator of protein kinase C ζ signaling targeted by SV40 small t to promote cell growth and NF‐κB activation
Author(s) -
Sontag Estelle,
Sontag JeanMarie,
Garcia Alphonse
Publication year - 1997
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/16.18.5662
Subject(s) - biology , regulator , phosphatase , kappa , microbiology and biotechnology , signal transduction , protein kinase a , nfkb1 , cell growth , kinase , protein phosphatase 2 , phosphorylation , biochemistry , transcription factor , gene , linguistics , philosophy
We have reported that inhibition of protein phosphatase 2A (PP2A) by expression of SV40 small t stimulates the mitogenic MAP kinase cascade. Here, we show that SV40 small t can substitute for tumor necrosis factor‐α (TNF‐α) or serum and stimulate atypical protein kinase C ζ (PKC ζ) activity, resulting in MEK activation, cell proliferation and NF‐κB‐dependent gene transcriptional activation in CV‐1 and NIH 3T3 cells. These effects were abrogated by co‐expression of kinase‐deficient PKC ζ and inhibition of phosphatidylinositol 3‐kinase p85α‐p110 by wortmannin, LY294002 and a dominant‐negative mutant of p85α. In contrast, expression of kinase‐inactive ERK2 inhibited small t‐dependent cell growth but was unable to abolish small t‐induced NF‐κB transactivation. Our results provide the first in vivo evidence for a critical regulatory role of PP2A in bifunctional PKC ζ signaling pathways controlled by phosphatidylinositol 3‐kinase. Constitutive activation of PKC ζ and NF‐κB following inhibition of PP2A supports new mechanisms by which SV40 small t promotes cell growth and transformation. By establishing PP2A as a key player in the response of cells to growth factors and stress signals like TNF‐α, our findings could explain why PP2A is a primary target utilized during SV40 infection to alter cellular behavior.