title: Regulation of MEK/ERK pathway output by subcellular localization of B-Raf.
abstract: The strength and duration of intracellular signalling pathway activation is a key determinant of the biological outcome of cells in response to extracellular cues. This has been particularly elucidated for the Ras/Raf/MEK [mitogen-activated growth factor/ERK (extracellular-signal-regulated kinase) kinase]/ERK signalling pathway with a number of studies in fibroblasts showing that sustained ERK signalling is a requirement for S-phase entry, whereas transient ERK signalling does not have this capability. A major unanswered question, however, is how a cell can sustain ERK activation, particularly when ERK-specific phosphatases are transcriptionally up-regulated by the pathway itself. A major point of ERK regulation is at the level of Raf, and, to sustain ERK activation in the presence of ERK phosphatases, sustained Raf activation is a requirement. Three Raf proteins exist in mammals, and the activity of all three is induced following growth factor stimulation of cells, but only B-Raf activity is maintained at later time points. This observation points to B-Raf as a regulator of sustained ERK activation. In the present review, we consider evidence for a link between B-Raf and sustained ERK activation, focusing on a potential role for the subcellular localization of B-Raf in this key physiological event.
authors.affiliation: Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Andreadi
authors.forename: Catherine
authors.initials: C
authors.lastname: Noble
authors.forename: Bipin
authors.initials: B
authors.lastname: Patel
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aguilar Hernandez
authors.forename: Kathryn
authors.initials: K
authors.lastname: Balmanno
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cook
authors.forename: Catrin
authors.initials: C
authors.lastname: Pritchard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf