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

Abstract

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.