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.

Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

“…Many regulators of ERK signal intensity and duration have been identified (Andreadi et al, 2012), such as the linkage of B-Raf to prolonged ERK activation (Tsukamoto et al, 2004). B-Raf is thought to prolong ERK signaling through a newly described adaptor molecule, Kidins220, which is expressed in T lineage progenitors and associates with both the pre-TCR and γδTCR (Deswal et al, 2013).…”

MAPKs and Signal Transduction in the Control of Gastrointestinal Epithelial Cell Proliferation and Differentiation

“…For example, the dual specificity phosphatase-6 (DUSP-6, also known as MKP-3) is a cytoplasmic MKP that has ERK1/2 as preferential target. Both MKPs and the scaffold proteins mentioned above are important to establish the magnitude and duration of signals, which also determine the output of MAPK pathway stimulation [10,12,13]. The different fates of PC12 pheocromocytoma cells in response to epidermal growth factor (EGF) and nerve growth factor (NGF) are classical examples of temporal control in ERK1/2 signaling, as EGF-induced transient activation of ERK stimulates PC12 cell proliferation, whereas NGF-sustained stimulus leads to cell differentiation [13].…”

PTEN regulation of ERK1/2 signaling in cancer

“…For instance, the continuous activation of epidermal growth factor receptor (EGFR) resulted in constitutive activation of downstream target ERK1/2. Likewise, a mutation in the proto-oncogene B-Raf rendered it constitutively active, and as a result, downstream targets like the ERK1/2 pathway also became constitutively active and tumorigenic (40). …”