TPL-2 ACTS IN CONCERT WITH RAS AND RAF-1 TO ACTIVATE MITOGEN-ACTIVATED PROTEIN-KINASE

Mitogenic signals initiated at the plasma membrane by extracellular fa ctors acting on receptor tyrosine kinases or G protein-coupled recepto rs are transmitted to the nucleus through an intricate signaling netwo rk. Components of this network participate, upon stimulation, in a com plex array of phosphorylation-dependent protein-protein interactions w hich leads to the formation of transient multimolecular complexes. Com plexes containing products of the protooncogenes ras and raf-1 and the protein kinase MEK-1 activate the mitogen-activated protein kinases ( MAPKs), which play a central role in the integration of different mito genic signals by directly phosphorylating cytoplasmic and nuclear targ ets. In this report we present evidence that the kinase encoded by the tumor progression locus 2 gene (Tpl-2) contributes to the activation of the MAPK cascade. MAPK activation induced by the Tpl-2 protein is b locked by dominant negative mutants of Ras and Raf-1, whereas a kinase -deficient Tpl-2 mutant downregulates mitogenic signals induced by v-H a Ras or v-Raf. These data suggest that Tpl-2 activates the MAPK casca de, perhaps through its participation in the assembly of Ras/Raf-1 con taining multimolecular complexes.