Rsk1 mediates a MEK-MAP kinase cell survival signal

Background: Growth factors activate an array of cell survival signaling pat hways. Mitogen-activated protein (MAP) kinases transduce signals emanating from their upstream activators MAP kinase kinases (MEKs). The MEK-MAP kinas e signaling cassette is a key regulatory pathway promoting cell survival. T he downstream effecters of the mammalian MEK-MAP kinase cell survival signa l have not been previously described. Results: We identify here a pro-survival role for the serine/threonine kina se Rsk1, a downstream target of the MEK-MAP kinase signaling pathway. In ce lls that are dependent on interleukin-3 (IL-3) for survival, pharmacologica l inhibition of MEKs antagonized the IL-3 survival signal. In the absence o f IL-3, a kinase-dead Rsk1 mutant eliminated the survival effect afforded b y activated MEK, Conversely, a novel constitutively active Rsk1 allele rest ored the MEK-MAP kinase survival signal. Experiments in vitro and in vivo d emonstrated that Rsk1 directly phosphorylated the pro-apoptotic protein Bad at the serine residues that, when phosphorylated, abrogate Bad's pro-apopt otic function. Constitutively active Rsk1 caused constitutive Bad phosphory lation and protection from Bad-modulated cell death. Kinase-inactive Rsk1 m utants antagonize Bad phosphorylation. Bad mutations that prevented phospho rylation by Rsk1 also inhibited Rsk1-mediated cell survival. Conclusions: These data support a model in which Rsk1 transduces the mammal ian MEK-MAP kinase signal in part by phosphorylating Bad.