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.
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February 2012
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Conference Article|
January 19 2012
Regulation of MEK/ERK pathway output by subcellular localization of B-Raf
Catherine Andreadi;
Catherine Andreadi
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Catherine Noble;
Catherine Noble
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Bipin Patel;
Bipin Patel
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Hong Jin;
Hong Jin
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Maria M. Aguilar Hernandez;
Maria M. Aguilar Hernandez
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
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Kathryn Balmanno;
Kathryn Balmanno
†Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
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Simon J. Cook;
Simon J. Cook
†Laboratory of Signalling and Cell Fate, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, U.K.
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Catrin Pritchard
Catrin Pritchard
1
*Department of Biochemistry, Henry Wellcome Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, U.K.
1To whom correspondence should be addressed (email cap8@le.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 16 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (1): 67–72.
Article history
Received:
June 16 2011
Citation
Catherine Andreadi, Catherine Noble, Bipin Patel, Hong Jin, Maria M. Aguilar Hernandez, Kathryn Balmanno, Simon J. Cook, Catrin Pritchard; Regulation of MEK/ERK pathway output by subcellular localization of B-Raf. Biochem Soc Trans 1 February 2012; 40 (1): 67–72. doi: https://doi.org/10.1042/BST20110621
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