ERK and p38 pathways regulate amino acid signalling

Biochim Biophys Acta. 2008 Dec;1783(12):2241-54. doi: 10.1016/j.bbamcr.2008.08.011. Epub 2008 Sep 6.

Abstract

The ribosomal protein S6 kinase 1 (S6K1) is emerging as a common downstream target of signalling by hormones and nutrients such as insulin and amino acids. Here, we have investigated how amino acids signal through the S6K1 pathway. First, we found that a commercial anti-phospho-Thr389-S6K1 antibody detects an 80-90 kDa protein that is rapidly phosphorylated in response to amino acids. Unexpectedly, this phosphorylation was insensitive to both mTOR and PI-3 kinase inhibitors, and knockdown experiments showed that this protein was not S6K1. Looking for candidate targets of this phosphorylation, we found that amino acids stimulated phosphorylation of RSK and MSK kinases at residues that are homologous to Thr389 in S6K1. In turn, these phosphorylations required the activity of either p38 or ERK MAP kinases, which could compensate for each other. Moreover, we show that these MAP kinases are also needed for the amino acid-induced phosphorylation of S6K1 at Thr421/Ser424, as well as for that of S6K1 substrate, the S6 ribosomal protein. Consistent with these results, concomitant inhibition of p38 and ERK pathways also antagonised the well-known effects of amino acids on the process of autophagy. Altogether, these findings demonstrate a previously unknown role for MAP kinases in amino acid signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism*
  • Androstadienes / pharmacology
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Immunosuppressive Agents / pharmacology
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Plasmids
  • Protein Transport
  • RNA, Small Interfering / pharmacology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology
  • Wortmannin
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Amino Acids
  • Androstadienes
  • Antibiotics, Antineoplastic
  • Immunosuppressive Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • RPS6KA1 protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Sirolimus
  • Wortmannin