A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1

J Biol Chem. 2009 Aug 7;284(32):21412-24. doi: 10.1074/jbc.M109.026013. Epub 2009 Jun 11.

Abstract

Autophagy-essential proteins are the molecular basis of protective or destructive autophagy machinery. However, little is known about the signaling mechanisms governing these proteins and the opposing consequences of autophagy in mammals. Here we report that a non-canonical MEK/ERK module, which is positioned downstream of AMP-activated protein kinase (AMPK) and upstream of tuberous sclerosis complex (TSC), regulates autophagy by regulating Beclin 1. Depletion of ERK partially inhibited autophagy, whereas specific inhibition on MEK completely inhibited autophagy. MEK could bypass ERK to promote autophagy. Basal MEK/ERK activity conferred basal Beclin 1 by preventing disassembly of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. Activation of MEK/ERK by AMPK upon autophagy stimuli disassembled mTORC1 via binding to and activating TSC but disassembled mTORC2 independently of TSC. Inhibition of mTORC1 or mTORC2 by transiently or moderately activated MEK/ERK caused moderately enhanced Beclin 1 resulting in cytoprotective autophagy, whereas inhibition of both mTORC1 and mTORC2 by sustained MEK/ERK activation caused strongly pronounced Beclin 1 leading to cytodestructive autophagy. Our findings thus propose that the AMPK-MEK/ERK-TSC-mTOR pathway regulation of Beclin 1 represents different thresholds responsible for a protective or destructive autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology*
  • Autophagy*
  • Beclin-1
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression Regulation*
  • Humans
  • K562 Cells
  • MAP Kinase Kinase Kinases / metabolism*
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Multiprotein Complexes
  • Proteins
  • Rats
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • CRTC2 protein, human
  • Membrane Proteins
  • Multiprotein Complexes
  • Proteins
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases