The proto-oncogene encoding the Tpl-2 kinase was identified as a common target of proviral integration in MoMuLV-induced rat T cell lymphomas. Proviral integration in Tpl-2 occurs during tumor progression in 22.5% of the tested thymonas, and the mRNA transcribed from the rearranged Tpl-2 locus encodes a C-terminally truncated protein. Recent studies using Tpl-2 transgenic mice confirmed that Tpl-2 is a highly oncogenic kinase whose oncogenic potential is induced by C-terminal truncation. Additional studies on the role of Tpl-2 in signal transduction showed that Tpl-2 is a mediator of TNFalpha signaling. Moreover, they showed that Tpl-2 interacts with the guanine nucleotide exchange factor Vav and activates the MAPK and JNK pathway as well as NF-kB. Through its effects on these signaling pathways Tpl-2 activates several promoters including its own promoter, the CMV major immediate early promoter, and the promoter of IL-2. Regarding the IL-2 promoter, it was shown that its activation was mediated by MAPK and JNK dependent signals as well as calcium/calmodulin dependent signals. Based on this information, experiments were designed to address the role of Tpl-2 in TNFalpha signaling, as well as in IL-2 expression and in the biology of neoplastic progression. The long term objective of this project is to use the Tpl-2 protoncogene as a probe to explore the biology of the immune system and the pathobiology of neoplasia with emphasis on tumor progression and metastasis.