Rsk1 mediates a MEK-MAP kinase cell survival signal. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • February 10, 2000

Research

keywords

  • Apoptosis
  • MAP Kinase Kinase Kinases
  • MAP Kinase Signaling System
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa

Identity

Scopus Document Identifier

  • 0034628612

Digital Object Identifier (DOI)

  • 10.1016/s0960-9822(00)00310-9

PubMed ID

  • 10679322

Additional Document Info

volume

  • 10

issue

  • 3