Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

Shindo, Yoichi; Iwamoto, Kenji; Mouri, Kazunari; Hibino, Kayo; Tomita, Masaru; Kosako, Hidetaka; Sako, Yasushi; Takahashi, Koichi

doi:10.1038/ncomms10485

Cited by 58 publications

(48 citation statements)

References 50 publications

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“…While Spry2/4 and Etv4/5 are detected in all ICM cells, Dusp4 expression correlates with PrE (Figure 6B and S6). These downstream targets can regulate the MAPK/ERK cascade via positive and negative feedback to produce specific context-dependent responses (Brewer et al, 2016; Buday et al, 1995; Ekerot et al, 2008; Kholodenko, 2006; Shindo et al, 2016; Vasudevan and Soriano, 2016). Therefore, the association of EPI- and PrE-biased cells with distinct targets indicates that differential levels of FGF signaling in lineage-biased cells may be augmented by distinct feedback (Figure 6A).…”

Section: Discussionmentioning

confidence: 99%

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

2017

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FGF4 is the key signal driving specification of primitive endoderm (PrE) versus pluripotent epiblast (EPI) within the inner cell mass (ICM) of the mouse blastocyst. To gain insight into the receptor(s) responding to FGF4 within ICM cells, we combined single-cell-resolution quantitative imaging with single-cell transcriptomics of wild-type and Fgf receptor (Fgfr) mutant embryos. Despite the PrE-specific expression of FGFR2, it is FGFR1, expressed by all ICM cells, which is critical for establishment of a PrE identity. Signaling through FGFR1 is also required to constrain levels of the pluripotency-associated factor NANOG in EPI cells. However, the activity of both receptors is required for lineage establishment within the ICM. Gene expression profiling of 534 single ICM cells identified distinct downstream targets associated with each receptor. These data lead us to propose a model whereby unique and additive activities of FGFR1 and FGFR2 within the ICM coordinate establishment of two distinct lineages.

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Section: Discussionmentioning

confidence: 99%

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

2017

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“…Previous studies in mammalian cells have shown specific feedback mechanisms that modulate nuclear ERK activity. These mechanisms include the facilitation of nuclear import and export of ERK by EGF signals (Ando, Mizuno, & Miyawaki, ) and the conversion of graded ERK activity in response to different levels of RTK stimulus into a threshold response of nuclear ERK through facilitated nuclear translocation (Shindo et al, ). The latter study demonstrated that the facilitated nuclear translocation achieves the nuclear accumulation of ERK within 8 min of RTK stimulation at the threshold concentration of ~0.05 mg/ml EGF.…”

Section: Discussionmentioning

confidence: 99%

Automated FRET quantification shows distinct subcellular ERK activation kinetics in response to graded EGFR signaling in Drosophila

et al. 2019

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Threshold responses to an activity gradient allow a single signaling pathway to yield multiple outcomes. Extracellular signal‐regulated kinase (ERK) is one such signal, which couples receptor tyrosine kinase signaling with multiple cellular responses in various developmental processes. Recent advances in the development of fluorescent biosensors for live imaging have enabled the signaling activities accompanying embryonic development to be monitored in real time. Here, we used an automated computational program to quantify the signals of a fluorescence resonance energy transfer (FRET) reporter for activated ERK, and we used this system to monitor the spatio‐temporal dynamics of ERK during neuroectoderm patterning in Drosophila embryos. We found that the cytoplasmic and nuclear ERK activity gradients show distinct kinetics in response to epidermal growth factor receptor activation. The ERK activation patterns implied that the cytoplasmic ERK activity is modulated into a threshold response in the nucleus.

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“…D. Weber, Raben, Phillips, & Baldassare, 1997). The graded mammalian ERK activation in response to cellular stimuli is converted to a switch-like mechanism to control c-fos induction during the immediate-early gene response (Mackeigan, Murphy, Dimitri, & Blenis, 2005), in part through regulation of ERK nuclear translocation (Shindo et al, 2016). With only transient ERK activation, c-Fos and other IEG protein products are synthesized, but are unstable and quickly become degraded (Murphy et al, 2002).…”

Section: Erk Substratesmentioning

confidence: 99%

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

Eblen

2018

Advances in Cancer Research

151

104

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The extracellular regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that are involved in regulating cellular signaling in both normal and pathological conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates. In this review, I will discuss some of what has been discovered about the members of the Ras to ERK pathway, including regulation of their activation by growth factors and cell adhesion pathways. Looking downstream of ERK activation, I will also highlight some of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration, and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis.

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Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling

Cited by 58 publications

References 50 publications

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

Automated FRET quantification shows distinct subcellular ERK activation kinetics in response to graded EGFR signaling in Drosophila

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

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