Tumour cell survival signalling by the ERK1/2 pathway

Cell Death Differ. 2009 Mar;16(3):368-77. doi: 10.1038/cdd.2008.148. Epub 2008 Oct 10.


Several advances in recent years have focused increasing attention on the role of the RAF-MEK-ERK1/2 pathway in promoting cell survival. The demonstration that BRAF is a human oncogene mutated at high frequency in melanoma, thyroid and colon cancer has provided a pathophysiological context, whilst the description of potent and highly selective inhibitors of BRAF or MEK has allowed a more informed and rational intervention in both normal and tumour cells. In addition, separate studies have uncovered new mechanisms by which the ERK1/2 pathway can control the activity or abundance of members of the BCL-2 protein family to promote cell survival. It is now apparent that various oncogenes co-opt ERK1/2 signalling to de-regulate these BCL-2 proteins and this contributes to, and even underpins, survival signalling in some tumours. New oncogene-targeted therapies allow direct or indirect inhibition of ERK1/2 signalling and can cause quite striking tumour cell death. In other cases, inhibition of the ERK1/2 pathway may be more effective in combination with other conventional and novel therapeutics. Here, we review recent advances in our understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Cell Survival*
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Membrane Proteins / metabolism
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Oncogenes
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Stability
  • Transcription, Genetic
  • bcl-Associated Death Protein / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-Associated Death Protein
  • ErbB Receptors
  • Fusion Proteins, bcr-abl
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • ras Proteins