TPL-2 IS AN ONCOGENIC KINASE THAT IS ACTIVATED BY CARBOXY-TERMINAL TRUNCATION

Provirus insertion in the last intron of the Tpl-2 gene in retrovirus- induced rat T-cell lymphomas results in the enhanced expression of a c arboxy-terminally truncated Tpl-2 kinase. Here we show that the trunca ted protein exhibits an approximately sevenfold higher catalytic activ ity and is two- to threefold more efficient in activating the MAPK and SAPK pathways relative to the wild-type protein. The truncated Tpl-2 protein and a GST fusion of the Tpl-2 carboxy-terminal tail interact w hen coexpressed in Sf9 cells. Their interaction down-regulates the kin ase activity of the truncated protein suggesting that tail-directed in tramolecular interactions regulate the Tpl-2 kinase. Tpl-2 transgenic mice expressing the wild-type protein from the proximal Lck promoter f ail to show a biological phenotype, whereas mice expressing the trunca ted protein develop large-cell lymphoblastic lymphomas of T-cell origi n. These results show that Tpl-2 is an oncogenic kinase that is activa ted by carboxy-terminal truncation.