ACTIVATION OF MEK-1 AND SEK-1 BY TPL-2 PROTO-ONCOPROTEIN, A NOVEL MAPKINASE KINASE KINASE

The Tpl-2 protein serine/threonine kinase was originally identified, i n a C-terminally deleted form, as the product of an oncogene associate d with the progression of Moloney murine leukemia virus-induced T cell lymphomas in rats. The kinase domain of Tpl-2 is homologous to the Sa ccharomyces cerevisiae gene product, STE11, which encodes a MAP kinase kinase kinase. This suggested that Tpl-2 might have a similar activit y. Consistent with this hypothesis, immunoprecipitated Tpl-2 and Tpl-2 Delta C (a C-terminally truncated mutant) phosphorylated and activate d recombinant fusion proteins of the mammalian MAP kinase kinases, MEK -1 and SEK-1, in vitro. Furthermore, transfection of Tpl-2 into COS-1 cells or Jurkat T cells, markedly activated the MAP kinases, ERK-1 and SAP kinase (JNK), which are substrates for MEK-1 and SEK-1, respectiv ely, Tpl-2, therefore, is a MAP kinase kinase kinase which can activat e two MAP kinase pathways. After Raf and Mos, Tpl-2 is the third serin e/threonine oncoprotein kinase that has been shown to function as a di rect activator of MEK-1.