Infection of bovine T cells and B cells with the intracellular protozoan parasite
IntroductionInfection of bovine T cells and B cells with the intracellular protozoan parasite Theileria parva induces a transformed phenotype with characteristics comparable to tumor cells. Hallmarks of transformation are the capacity of infected cells to proliferate in vitro in the absence of exogenous growth factors or antigenic stimulation. 1 Moreover, Theileria-infected leukocytes behave as invasive tumors in both scid 2 and in athymic, irradiated mice, 3,4 and they can form colonies in soft agar. Parasite-dependent regulation of host cell signal transduction pathways is thought to be critical in establishing the transformed phenotype of infected leukocytes. 5,6 Consistently, host cell c-Jun N-terminal kinase (JNK), but not Erk or p38 mitogen-activated protein (MAP) kinases, is activated constitutively in infected leukocytes. 7,8 JNK activation results in permanent up-regulation of Jun and Fos family proteins and induction of the transcription factors AP-1 8 and ATF-2. 9 Importantly, Theileria-induced transformation can be reverted by treatment with the theilericidal drug BW720c, 10 and the leukocytes then acquire a resting phenotype, or die of apoptosis, as reviewed in Dobbelaere and Heussler. 11 Reversion of the transformed state is an unusual feature for tumor cells, as cellular transformation is usually associated with genomic alterations (rearrangements/mutations) or stable insertion of foreign DNA. 12 Because the "transforming" stimulus can be eliminated by drug treatment, lymphocytes infected with T parva offer a rare opportunity to compare proliferative and antiapoptotic signaling pathways in transformed cells with those of isogenic resting cells.Src family members are a group of 9 nonreceptor tyrosine kinases that share a high degree of structural homology. Their molecules are organized into 3 major domains, which from the Nto the C-terminus, are a Src homology domain 3 (SH3) domain, a SH2 domain, and the tyrosine kinase (SH1) domain. 13 18 Their function is to convey extracellular signals through membrane-proximal compartments to cellular effector pathways; for review, see Brown and Cooper. 19 Src family kinases are modified by myristoylation and palmitoylation at their N-termini; these fatty acid residues direct the enzymes to membrane compartments 20 and particularly to Glycolipid Enriched Microdomains (GEMs), also called membrane rafts. 21 Recruitment to nonlipidic subcellular locations, such as the cytoskeleton, requires SH3 or SH2 domain-dependent interactions, which are thus important in bringing the kinase into proximity with specific substrates, but also in regulating their state of activation. 22,23 Src family kinases are negatively regulated by induction of a closed, inactive conformation. 13 Inhibitory phosphorylation of the C-terminal tyrosine 24 by the C-terminal Src kinase Csk [25][26][27] promotes binding of the SH2 domain and because of steric hindrance inactivates the kinase as reviewed in Shallowa...