Oscillatory dynamics of the extracellular signal-regulated kinase pathway

Shankaran, Harish; Wiley, H. Steven

doi:10.1016/j.gde.2010.08.002

Cited by 35 publications

(39 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These properties may explain why it has not been observed in previous studies. Differences in spatial and temporal components of ERK activation can lead to profoundly distinct functional effects (26,33,38). Our results also suggest that eIF3a can exert specific regulatory effects on the kinetics of ERK activation through its interaction with ␤-arrestin2.…”

Section: Discussionmentioning

confidence: 58%

Eukaryotic Translation Initiation Factor 3, Subunit a, Regulates the Extracellular Signal-Regulated Kinase Pathway

Reverter

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

The extracellular signal-regulated kinase (ERK) pathway participates in the control of numerous cellular processes, including cell proliferation. Since its activation kinetics are critical for to its biological effects, they are tightly regulated. We report that the protein translation factor, eukaryotic translation initiation factor 3, subunit a (eIF3a), binds to SHC and Raf-1, two components of the ERK pathway. The interaction of eIF3a with Raf-1 is increased by ␤-arrestin2 expression and transiently decreased by epidermal growth factor (EGF) stimulation in a concentration-dependent manner. The EGF-induced decrease in Raf-1-eIF3a association kinetically correlates with the time course of ERK activation. eIF3a interferes with Raf-1 activation and eIF3a downregulation by small interfering RNA enhances ERK activation, early gene expression, DNA synthesis, expression of neuronal differentiation markers in PC12 cells, and Ras-induced focus formation in NIH 3T3 cells. Thus, eIF3a is a negative modulator of ERK pathway activation and its biological effects. The extracellular signal-regulated kinase (ERK) pathway is involved in many fundamental cellular processes, including cell proliferation and transformation (5, 11). The activation sequence of the core components of the pathway is well characterized (32, 39). The pathway is typically activated by receptor tyrosine kinases, such as the epidermal growth factor (EGF) receptor (EGFR), which autophosphorylate at their intracellular kinase domains upon ligand binding. These phosphotyrosines serve as docking sites for adaptor proteins and signal transducers which activate the downstream pathways that mediate the biological effects of the ligands. The ERK pathway is initiated by the translocation of the guanine nucleotide exchange factor (GEF) SOS from the cytosol to the plasma membrane via the adaptor proteins SHC and Grb2 binding to specific phosphotyrosines at the EGFR. SOS then activates Ras, which binds to Raf kinases recruiting them to the membrane for activation. Raf activation is a complex process that is still not fully elucidated, and slightly different between the three Raf isoforms A-Raf, 〉-Raf, and Raf-1. A critical step in Raf-1 activation is the Ras-induced dephosphorylation of the inhibitory phospho-S259, which is required for the subsequent phosphorylation of the key activating site S338 (12, 13). Active Raf-1 phosphorylates MEK, which in turn phosphorylates ERK. ERK has Ͼ150 substrates in the cytosol and nucleus (45). This large number of substrates enables the pathway to carry out its highly pleiotropic functions, although it is still rather enigmatic as to how specificity in signaling and biological responses is produced. Nevertheless, it is thought that the activation kinetics, spatial organization, cross talk, and binding to scaffold proteins contribute to the generation of signaling specificity (5, 39). Thus, although the core pathway is well mapped, identification and analysis of the proteins that modulate these parameters is required in order to un...

show abstract

Section: Discussionmentioning

confidence: 58%

Eukaryotic Translation Initiation Factor 3, Subunit a, Regulates the Extracellular Signal-Regulated Kinase Pathway

Reverter

et al. 2012

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…69 A closely related phenomenon was recently observed in human mammary epithelial cells stimulated with low EGF doses, where total ERK2 nuclear levels (as observed by lowly expressed ERK2-GFP) oscillated with a period of approximately 15 minutes after ligand stimulation. 70,71 As primarily only activated ppERK is gives a log-linear relationship between ligand dose and active receptor levels spanning approximately five decades (Fig. 3).…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

Biology using engineering tools

Birtwistle

Kölch

2011

Cell Cycle

View full text Add to dashboard Cite

“…Cyclic expression in the PSM of the ERK phosphatase dual specificity phosphatase 4 (Dusp4), itself an FGF target gene, may be responsible for the observed rhythm in ERK phosphorylation (Niwa et al, 2007;Niwa et al, 2011). Interestingly, sustained oscillations in the ERK signaling network have been observed in other contexts (Shankaran and Wiley, 2010), but segmental defects have not been reported in Dusp4 mutant mice (AlMutairi et al, 2010), and the role of these intriguing phosphorylation cycles in the mouse segmentation clock remains unclear.In combination, these results indicate that cyclic genes are the transcriptionally oscillating component of a larger molecular segmentation clock. Whenever cyclic traveling wave patterns are disrupted, normal somitogenesis is also disrupted.…”

mentioning

confidence: 99%

Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock

2012

View full text Add to dashboard Cite

The segmentation clock is an oscillating genetic network thought to govern the rhythmic and sequential subdivision of the elongating body axis of the vertebrate embryo into somites: the precursors of the segmented vertebral column. Understanding how the rhythmic signal arises, how it achieves precision and how it patterns the embryo remain challenging issues. Recent work has provided evidence of how the period of the segmentation clock is regulated and how this affects the anatomy of the embryo. The ongoing development of realtime clock reporters and mathematical models promise novel insight into the dynamic behavior of the clock.Key words: Gradient, Modeling, Negative feedback, Oscillator, Signaling, Somitogenesis IntroductionThe segmented anatomy of the vertebrate embryo is evident in the two bilaterally symmetrical rows of somites that flank the notochord along the body axis. These blocks of mesodermal cells give rise primarily to bone, muscle and skin of the adult body, which is correspondingly segmented. Somitogenesis is a rhythmic and sequential process in which each successive bilateral somite pair segregates at a regular time interval from the anterior end of the pre-somitic mesoderm (PSM, see Glossary, Box 1) as the body axis elongates (Fig. 1A,B). Somitogenesis has long been of interest to developmental biologists because it involves the coordination of patterning and growth of a tissue by a regularly repeated morphogenetic process. The topic of this review is the molecular segmentation clock that underlies this periodicity. The segmentation clock has attracted the attention of those interested in biological clocks and the molecular mechanisms of developmental timing, as well as those studying the function and stability of rapidly acting genetic circuits, and the interplay between the properties of single cells and their collective behavior at the tissue level. Finally, the rhythmic nature of the process is the seed for a theoretical interest in somitogenesis that is decades old and now promises a powerful synthesis of experiment and theory that is emblematic of modern embryology.This review first provides an overview of somitogenesis, then describes the prevailing dynamic model for somitogenesis, the Clock and Wavefront mechanism, its molecular phenomenology Development 139, 625-639 (2012) REVIEW Box 1. GlossaryBiological oscillator. A system that generates a periodic variation in the state of a cell, tissue or organism. The vibrating stereocillia bundles of inner ear hair cells, the contraction cycle of cardiac muscle cells, circadian clocks and rhythmic neuronal circuits are all biological oscillators. Coupling. Communication between neighboring oscillators that leads to mutual adjustment of their frequencies. For example, activation of Notch receptors in a presomitic mesoderm cell by Delta from neighboring cells can affect the dynamics of Notch pathway components in the target cell. Frequency profile. Dependence of the frequency of the oscillators in an array on their position. In the segmentat...

show abstract

Oscillatory dynamics of the extracellular signal-regulated kinase pathway

Cited by 35 publications

References 43 publications

Eukaryotic Translation Initiation Factor 3, Subunit a, Regulates the Extracellular Signal-Regulated Kinase Pathway

Eukaryotic Translation Initiation Factor 3, Subunit a, Regulates the Extracellular Signal-Regulated Kinase Pathway

Biology using engineering tools

Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock

Contact Info

Product

Resources

About