RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation

Biochem J. 2012 Oct 1;447(1):159-66. doi: 10.1042/BJ20120938.

Abstract

The extent and duration of MAPK (mitogen-activated protein kinase) signalling govern a diversity of normal and aberrant cellular outcomes. Genetic and pharmacological disruption of the MAPK-activated kinase RSK (ribosomal S6 kinase) leads to elevated MAPK activity indicative of a RSK-dependent negative feedback loop. Using biochemical, pharmacological and quantitative MS approaches we show that RSK phosphorylates the Ras activator SOS1 (Son of Sevenless homologue 1) in cultured cells on two C-terminal residues, Ser(1134) and Ser(1161). Furthermore, we find that RSK-dependent SOS1 phosphorylation creates 14-3-3-binding sites. We show that mutating Ser(1134) and Ser(1161) disrupts 14-3-3 binding and modestly increases and extends MAPK activation. Together these data suggest that one mechanism whereby RSK negatively regulates MAPK activation is via site-specific SOS1 phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism*
  • Amino Acid Substitution
  • Animals
  • Binding Sites
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Models, Biological
  • Mutagenesis, Site-Directed
  • NIH 3T3 Cells
  • Phosphorylation
  • Rats
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribosomal Protein S6 Kinases / metabolism*
  • SOS1 Protein / chemistry
  • SOS1 Protein / genetics
  • SOS1 Protein / metabolism*
  • Serine / chemistry

Substances

  • 14-3-3 Proteins
  • Recombinant Proteins
  • SOS1 Protein
  • Serine
  • Ribosomal Protein S6 Kinases