SHP-2 Regulates Cell Growth by Controlling the mTOR/S6 Kinase 1 Pathway

J Biol Chem. 2007 Mar 9;282(10):6946-53. doi: 10.1074/jbc.M608338200. Epub 2007 Jan 17.

Abstract

Cell growth (accumulation in cell mass) ensues through the promotion of macromolecular biosynthesis. S 6 ribosomal kinase 1 (S6K1), which is activated by the mammalian target of rapamycin, is critical for cell growth. The early events that control S6K1 signaling remain unclear. Here we show that SHP-2 suppresses S6K1 activity under conditions of growth factor deprivation. We show that under conditions of growth factor deprivation, S6K1 activity was increased in fibroblasts lacking functional SHP-2 and in cells where knock down of SHP-2 expression was established by small interference RNA. Consistent with these findings, fibroblasts lacking functional SHP-2 exhibited increased cell size as compared with wild type cells. Growth factor deprivation reduces cellular energy, and the energy-sensing 5'-AMP-activated protein kinase (AMPK) negatively regulates S6K1. We found that SHP-2 promoted AMPK activity under conditions of growth factor deprivation (low energy), suggesting that SHP-2 negatively regulates S6K1 via an AMPK-dependent pathway. These results implicate SHP-2 as an early mediator in the S6K1 signaling pathway to limit cell growth in low energy states.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenylate Kinase / physiology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Cell Proliferation
  • Elongation Factor 2 Kinase
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Kinases / physiology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / physiology*
  • Ribosomal Protein S6 Kinases, 70-kDa / physiology*
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Eef2k protein, mouse
  • Elongation Factor 2 Kinase
  • Adenylate Kinase
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse