Rsk1 mediates a MEK-MAP kinase cell survival signal.
BACKGROUND
Growth factors activate an array of cell survival signaling pathways. Mitogen-activated protein (MAP) kinases transduce signals emanating from their upstream activators MAP kinase kinases (MEKs). The MEK-MAP kinase signaling cassette is a key regulatory pathway promoting cell survival. The downstream effectors of the mammalian MEK-MAP kinase cell survival signal have not been previously described.


RESULTS
We identify here a pro-survival role for the serine/threonine kinase Rsk1, a downstream target of the MEK-MAP kinase signaling pathway. In cells that are dependent on interleukin-3 (IL-3) for survival, pharmacological inhibition of MEKs antagonized the IL-3 survival signal. In the absence of IL-3, a kinase-dead Rsk1 mutant eliminated the survival effect afforded by activated MEK. Conversely, a novel constitutively active Rsk1 allele restored the MEK-MAP kinase survival signal. Experiments in vitro and in vivo demonstrated that Rsk1 directly phosphorylated the pro-apoptotic protein Bad at the serine residues that, when phosphorylated, abrogate Bad's pro-apoptotic function. Constitutively active Rsk1 caused constitutive Bad phosphorylation and protection from Bad-modulated cell death. Kinase-inactive Rsk1 mutants antagonize Bad phosphorylation. Bad mutations that prevented phosphorylation by Rsk1 also inhibited Rsk1-mediated cell survival.


CONCLUSIONS
These data support a model in which Rsk1 transduces the mammalian MEK-MAP kinase signal in part by phosphorylating Bad.
Shimamura
A
A
Department of Cell Biology, Department of Pediatric Hematology and Oncology, Harvard Medical School, Dana Farber Cancer Institute, Boston 02115, USA.
Ballif
B A
BA
Richards
S A
SA
Blenis
J
J
D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology / Q000502:physiology; D007668:Kidney; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D010957:Plasmids; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D015398:Signal Transduction; D014162:Transfection; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D002352:Carrier Proteins; D007377:Interleukin-3; D051025:bcl-Associated Death Protein; C069329:RPS6KA1 protein, human; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020930:MAP Kinase Kinase Kinases