Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase

Abstract

Elongation factor 2 kinase (eEF2k) phosphorylates and inactivates eEF2. Insulin induces dephosphorylation of eEF2 and inactivation of eEF2 kinase, and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, mTOR. However, the signalling mechanisms underlying these effects are unknown. Regulation of eEF2 phosphorylation and eEF2k activity is lost in cells in which phosphoinositide-dependent kinase 1 (PDK1) has been genetically knocked out. This is not due to loss of mTOR function since phosphorylation of another target of mTOR, initiation factor 4E-binding protein 1, is not defective. PDK1 is required for activation of members of the AGC kinase family; we show that two such kinases, p70 S6 kinase (regulated via mTOR) and p90 RSK1 (activated by Erk), phosphorylate eEF2k at a conserved serine and inhibit its activity. In response to insulin-like growth factor 1, which activates p70 S6 kinase but not Erk, regulation of eEF2 is blocked by rapamycin. In contrast, regulation of eEF2 by stimuli that activate Erk is insensitive to rapamycin, but blocked by inhibitors of MEK/Erk signalling, consistent with the involvement of p90 RSK1 .

Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells

“…In contrast to the previous report, S6K T389 phosphorylation was only slightly inhibited by BX-795 -this could reflect differences in the regulation of mTORC1 activity in PC3 cancer cells versus ES cells. Consistent with this, previous reports have shown little alterations in mTORC1 activity in ES cells lacking PDK1 [24,25].…”

Effects of bisindolylmaleimide PKC inhibitors on p90RSK activity in vitro and in adult ventricular myocytes

“…eEF2 is a cytoplasmic protein that catalyses the movement of the ribosome along mRNA during translation (which is essential for the extension of the polypeptide chain) and is regulated through phosphorylation by eEF2K (Ryazanov et al, 1997). eEF2K itself is negatively regulated by the upstream kinases p90 RSK and p70 S6K through phosphorylation at S366 (Wang et al, 2001b), such that activation of either pathway results in the inhibition of eEF2K activity and the consequent attenuation of eEF2 phosphorylation (Wang et al, 2001b). Interestingly, in the present study, the attenuation of eEF2 phosphorylation following heterologous expression of caMEK1 was not inhibited by GF109203X or Ro31-8220, despite the significant attenuation of eEF2K phosphorylation by both agents.…”

Regulation of the small GTPase Rheb by amino acids

“…mTOR controls protein synthesis and cell growth by phosphorylation of S6 kinase and 4EBP1 (Thomas and Hall, 1997;Fingar and Blenis, 2004). S6 kinase phosphorylates the ribosomal protein S6 as well as various other targets whose function remains unknown (Harada et al, 2001;Wang et al, 2001;Raught et al, 2004;Richardson et al, 2004). S6 phosphorylation was suggested to enhance the rate of translation of messenger RNAs containing 5 0 oligopyrimidine tracts (TOP mRNAs) (Grammer et al, 1996).…”