title: ERKs in cancer: friends or foes?
abstract: The extracellular signal-regulated kinase ERK1 and ERK2 (ERK1/2) cascade regulates a variety of cellular processes by phosphorylating multiple target proteins. The outcome of its activation ranges from stimulation of cell survival and proliferation to triggering tumor suppressor responses such as cell differentiation, cell senescence, and apoptosis. This pathway is intimately linked to cancer as several of its upstream activators are frequently mutated in human disease and are shown to accelerate tumorigenesis when engineered in the mouse genome. However, measurement of activated ERKs in human cancers or mouse models does not always support a role in tumorigenesis, and data consistent with a role in tumor suppression have been reported as well. The intensity of ERK signaling, negative feedback loops that regulate the pathway, and cross-talks with other signaling pathways, seem to be of primary importance in determining the final cellular outcome. Cell senescence, a putative tumor-suppression mechanism, depends on high-intensity ERK signals that trigger phosphorylation-dependent protein degradation of multiple proteins required for cell-cycle progression. This response may be circumvented during carcinogenesis by a variety of mechanisms, some of them yet to be discovered, which in essence turn ERK functions from tumor suppression to tumor promotion. The use of pharmacologic inhibitors targeting this pathway must be carefully evaluated so they are applied to cases in which ERKs are mainly oncogenic.
authors.affiliation: Authors' Affiliations: Département de Biochimie et Médecine Moléculaire; Department of Pharmacology and Program in Molecular Biology, Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal, Québec, Canada; and Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deschênes-Simard
authors.forename: Filippos
authors.initials: F
authors.lastname: Kottakis
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D048049:Extracellular Signal-Regulated MAP Kinases