However, because ERK is activated by phosphorylation by a host of divergent extracellular signals, more complex modes of regulation must exist in order to direct ERK activity toward appropriate responses. Raf kinases are activated through the GTPase Ras, which is activated downstream of extracellular signals such as Epidermal Growth Factor (EGF) ( Roskoski, 2012 Canagarajah et al., 1997).
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ERK is phosphorylated by the protein kinase mitogen-activated protein kinase kinase (MEK), which is first activated by the protein kinase Raf. The canonical mode of regulation is activation by phosphorylation at the end of a kinase cascade. The variety of processes induced through the ERK pathway presents a conundrum: how do extracellular cues specifically regulate the ERK pathway to induce the proper cellular response? However, studies have shown that ERK is also critically involved in regulating many other cellular processes, such as cell migration ( Mendoza et al., 2015 Mendoza et al., 2011), cell cycle progression ( Roberts et al., 2006 Chambard et al., 2007), autophagy ( Hui et al., 2016 Jo et al., 2014), metabolism ( Shin et al., 2015 Jiao et al., 2013), insulin secretion ( Ozaki et al., 2016), or even apoptosis ( Li, 2014 Cagnol and Chambard, 2010). This pathway is utilized by a host of different extracellular cues to regulate cellular processes such as proliferation, differentiation, and survival ( Keshet and Seger, 2010 Roskoski, 2012). Introductionĭue to its central role in signal transduction, extracellular-signal regulated kinase (ERK) has been the subject of intense study for over three decades ( Seger et al., 1991 Seger and Krebs, 1995) this research has elucidated many of the key mechanisms of ERK regulation. Our work strongly supports that spatial and temporal regulation of ERK activity is integrated to control signaling specificity from a single extracellular signal to multiple cellular processes. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. Using these sensors, we showed that EGF induces sustained ERK activity near the plasma membrane in sharp contrast to the transient activity observed in the cytoplasm and nucleus.
Reference manager 12 activation series#
To address this question, we have expanded the toolbox of Förster Resonance Energy Transfer (FRET)-based ERK biosensors by creating a series of improved biosensors targeted to various subcellular regions via sequence specific motifs to measure spatiotemporal changes in ERK activity.
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Given the wide distrubtion of ERK susbtrates across different subcellular compartments, it is important to understand how ERK activity is temporally regulated at specific subcellular locations. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. A variety of different signals induce specific responses through a common, extracellular-signal regulated kinase (ERK)-dependent cascade.