The Akt/PKB pathway is constitutively activated in Theileria-transformed leucocytes, but does not directly control constitutive NF-kappa B activation

The intracellular protozoan parasites Theileria parva and Theileria annulat a transform leucocytes by interfering with host cell signal transduction pa thways. They differ from tumour cells, however, in that the transformation process can be entirely reversed by elimination of the parasite from the ho st cell cytoplasm using a specific parasiticidal drug. We investigated the state of activation of Akt/PKB, a downstream target of PI3-K-generated phos phoinositides, in Theileria-transformed leucocytes. Akt/PKB is constitutive ly activated in a PI3-K- and parasite-dependent manner, as judged by the sp ecific phosphorylation of key residues, in vitro kinase assays and its cell ular distribution. In previous work, we demonstrated that the parasite indu ces constitutive activation of the transcription factor NF-kappaB, providin g protection against spontaneous apoptosis that accompanies transformation. In a number of other systems, a link has been established between the PI3K -Akt/PKB pathway and NF-kappaB activation, resulting in protection against apoptosis. In Theileria-transformed leucocytes, activation of the NF-kappaB and the PI3-K-Akt/PKB pathways are not directly linked. The PI3-K-Akt/PKB pathway does not contribute to the persistent induction of I kappaB alpha p hosphorylation, NF-kappaB DNA-binding or transcriptional activity. We show that the two pathways are downregulated with different kinetics when the pa rasite is eliminated from the host cell cytoplasm and that NF-kappaB-depend ent protection against apoptosis is not dependent on a functional PI3-K-Akt /PKB pathway. We also demonstrate that Akt/PKB contributes, at least in par t, to the proliferation of Theileria-transformed T cells.