Signaling through RAS-RAF-MEK-ERK: From basics to bedside

Armin Zebisch, Armin P. Czernilofsky, György Keri, Julja Smigelskaite, Heinz Sill, Jakob Troppmair

Research output: Contribution to journalReview article

81 Citations (Scopus)

Abstract

Aberrant signaling caused by mutations in the RAS-RAF-MEK-ERK pathway and its upstream activators critically contributes to human tumor development. Strategies, which aim at inhibiting hyperactive signaling molecules, appear conceptually straight forward, but their translation into clinical practice has been hampered by many setbacks. Understanding structure, function and regulation of this intracellular pathway as well as its crosstalk with other signaling activities in the cell will be essential to ensure reasonable usage of new therapeutic possibilities. This review provides an understanding of this signaling cascade as revealed by genetic and biochemical approaches and discusses the existing or arising possibilities to interfere with unphysiological activation in cancer. Signaling aberrations and signal transduction therapies will be discussed exemplary for two types of hematological neoplasia, acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). In the future understanding the role of tumor stem cells, both as a source of tumor recurrence and tumor heterogeneity, the signals controlling their fate as well as epigenetic changes in cancer will be the next critical steps to further advance the applicability of these novel therapeutic strategies.

Original languageEnglish
Pages (from-to)601-623
Number of pages23
JournalCurrent medicinal chemistry
Volume14
Issue number5
DOIs
Publication statusPublished - Feb 1 2007

Keywords

  • Acute myeloid leukemia
  • BAY 43-9006
  • C-RAF
  • Cytoplasmic cascade
  • Guanine nucleotide exchange factors (GEFs)
  • Non-receptor protein tyrosine kinase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Zebisch, A., Czernilofsky, A. P., Keri, G., Smigelskaite, J., Sill, H., & Troppmair, J. (2007). Signaling through RAS-RAF-MEK-ERK: From basics to bedside. Current medicinal chemistry, 14(5), 601-623. https://doi.org/10.2174/092986707780059670