title: It takes two to tango--signalling by dimeric Raf kinases.
abstract: Raf kinases function downstream of Ras proteins to activate the MEK-ERK pathway which is deregulated in a large number of human cancers. Raf inhibitors are clinically highly effective for the treatment of cancer and melanoma in particular, but have unexpected side effects that include a paradoxical activation of the ERK pathway. These effects seem to be related to the heterodimerization of Raf-1 and B-Raf kinases. Here, we discuss the role of Raf dimerization as part of the physiological activation mechanism of Raf kinases, the mechanism of Raf dimerization induced by drugs, and the implications of dimerization for drug therapies targeting Raf kinases.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland. angela.baljuls@ucd.ie
authors.forename: Angela
authors.initials: A
authors.lastname: Baljuls
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D055503:Protein Multimerization; D015398:Signal Transduction; D048490:raf Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D048490:raf Kinases