Genetic Engineering

Volume 24 of the series Genetic Engineering: Principles and Methods pp 49-66

Regulation of the Ras-MAPK Pathway at the Level of Ras and Raf

  • Hark VikisAffiliated withDepartment of Biological Chemistry, University of Michigan Medical School
  • , Kun-Liang GuanAffiliated withDepartment of Biological Chemistry, University of Michigan Medical SchoolInstitute of Gerontology, University of Michigan

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Cells use a variety of intracellular signaling pathways to interpret extracellular signals and translate them into cellular responses. The Ras-mitogen activated protein kinase (MAPK) pathway is a commonly-used intracellular signaling pathway used by eukaryotic cells to regulate such processes as cell growth, differentiation and survival (1,2). At the apex of the pathway is the small GTPase Ras whose activation state regulates a hierarchical three-kinase module comprised of the MAP kinase kinase kinase (MAPKKK), Raf, which phosphorylates and activates the MAP kinase kinase (MAPKK), MEK, which in turn phosphorylates and activates the MAP kinase (MAPK), ERK. How Ras activates Raf is the most complicated and contentious step in the pathway and has not been fully understood. Current findings suggest that activated Ras binds and recruits Raf to the plasma membrane where a coordinated series of phosphorylation events, protein-protein interactions and conformational changes occur to induce full activity. The past few years have led to the identification of new Raf phosphorylation sites that positively and negatively regulate Raf activity. In addition, genetic experiments in Drosophila and C.elegans have identified new proteins that modulate signaling at the level of Ras and Raf.