title: The importance of Raf dimerization in cell signaling.
abstract: The Raf family of protein kinases are key signaling intermediates, acting as a central link between the membrane-bound Ras GTPases and the downstream kinases MEK and ERK. Raf kinase regulation is well-known for its complexity but only recently has it been realized that many of the mechanisms involved in Raf regulation also modulate Raf dimerization, now acknowledged to be a required step for Raf signaling in multiple cellular contexts. Recent studies have shown that Raf dimerization is necessary for normal Ras-dependent Raf kinase activation and contributes to the pathogenic function of disease-associated mutant Raf proteins with all but high intrinsic kinase activity. Raf dimerization has also been found to alter therapeutic responses and disease progression in patients treated with ATP-competitive Raf inhibitors as well as certain other kinase-targeted drugs. This demonstration of clinical significance has stimulated the recent development of biosensor assays that can monitor inhibitor-induced Raf dimerization as well as studies demonstrating the therapeutic potential of blocking Raf dimerization.
authors.affiliation: Laboratory of Cell and Developmental Signaling; Center for Cancer Research; National Cancer Institute-Frederick; Frederick, MD USA.
authors.forename: Alyson K
authors.initials: AK
authors.lastname: Freeman
authors.affiliation: Laboratory of Cell and Developmental Signaling; Center for Cancer Research; National Cancer Institute-Frederick; Frederick, MD USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ritt
authors.affiliation: Laboratory of Cell and Developmental Signaling; Center for Cancer Research; National Cancer Institute-Frederick; Frederick, MD USA.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
mesh_terms: D019281:Dimerization; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins
keywords: B-Raf; C-Raf; ERK cascade; MEK; Raf family kinases; Ras