Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Maik-Rachline, Galia; Hacohen-Lev-Ran, Avital; Seger, Rony

doi:10.3390/ijms20051194

Cited by 158 publications

(112 citation statements)

References 125 publications

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“…Moreover, ERK1/2 is a major member of Mitogen-activated protein kinases (MAPKs) family, which are ubiquitous eukaryotic signal transduction enzymes that stimulate the pathways related to intracellular gene expression and acting kinases. Therefore, ERK1/2 mediates extracellular signals to the nucleus for the regulation of cell cycle and cell proliferation 40,41 . Increasing evidence shows that SGK1 is a member of the CALMP-dependent protein kinase A, cGMP-dependent kinase G, and phospholipid-dependent protein kinase C (AGC) family of serine or threonine protein kinases and serves as a downstream regulator in the PI3K pathway.…”

Section: Discussionmentioning

confidence: 99%

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics

Pan

Niu

Bhatti

et al. 2019

Sci Rep

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The encystment of many ciliates is an advanced survival strategy against adversity and the most important reason for ciliates existence worldwide. However, the molecular mechanism for the encystment of free-living ciliates is poorly understood. Here, we performed comparative transcriptomic analysis of dormant cysts and trophonts from Pseudourostyla cristata using transcriptomics, qRT-PCR and bioinformatic techniques. We identified 2565 differentially expressed unigenes between the dormant cysts and the trophonts. The total number of differentially expressed genes in GO database was 1752. The differential unigenes noted to the GO terms were 1993. These differential categories were mainly related to polyamine transport, pectin decomposition, cytoplasmic translation, ribosome, respiratory chain, ribosome structure, ion channel activity, and RNA ligation. A total of 224 different pathways were mapped. Among them, 184 pathways were upregulated, while 162 were downregulated. Further investigation showed that the calcium and AMPK signaling pathway had important induction effects on the encystment. In addition, FOXO and ubiquitin-mediated proteolysis signaling pathway jointly regulated the encystment. Based on these findings, we propose a hypothetical signaling network that regulates Pseudourostyla cristata encystment. Overall, these results provide deeper insights into the molecular mechanisms of ciliates encystment and adaptation to adverse environments.of Strepkiella histriomuscorum has been studied in the encystment and trophont stages through biochip technology, which suggested that cyst formation is associated with Ribosomal L7, Ribosomal acidic P2, Cathepsin B, Cathepsin H, Ubiquitin, Ca 2+ -ATPase and Actin1 7 . Other studies investigated the differential proteins of the cysts and the trophonts from Pseudourostyla cristata (P. cristata) using shotgun LC-MS/MS, finding the association of fibrillarin-like rRNA methylase, methylmalonyl-coenzyme mutase, ADP ribosylation factor, Rab12, MAPK-related kinase and KR multi-domain proteins with cyst formation 8 . However, the reports of systematically studying the genes and signaling pathways involved in the formation of ciliate cysts at the molecular level are rare 8 . In this study, we have investigated the molecular mechanism underlying the cyst formation in ciliates using comparative transcriptomic analysis, quantitative real-time PCR (qRT-PCR) and bioinformatic techniques. Furthermore, we have focused on the analysis of several important signaling pathways related to the encystment. Therefore, we have proposed a hypothetical network that regulates Pseudourostyla cristata encystment. Our study generates novel insights into the molecular mechanisms of the cyst formation in free-living ciliates.www.nature.com/scientificreports www.nature.com/scientificreports/ dormant cysts of P. cristata (Fig. 4). Validation of results by transcriptome sequencing showed that mRNA outcomes were consistent with the transcriptomic data of trophonts and dormant cysts in P. cristata (Fig. 4).

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Section: Discussionmentioning

confidence: 99%

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics

Pan

Niu

Bhatti

et al. 2019

Sci Rep

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“…An intriguing observation of our study is that SMO activation causes sustained repression of nuclear accumulation of bFGF-activated ERK. ERK has numerous targets in the nucleus [29], and the level of ERK activation in the nucleus was shown to balance proliferation (if nuclear ERK was high) versus differentiation (if nuclear ERK was low) in stem and progenitor cells [30]. Nuclear translocation of ERK is initiated by phosphorylation of its regulatory Tyr and Thr residues followed by exposure of the nuclear localization signal (NLS), subsequent phosphorylation by CKII, nuclear import through importin 7, and the regulation of up to 125 substrates (reviewed in [29]).…”

Section: Discussionmentioning

confidence: 99%

“…ERK has numerous targets in the nucleus [29], and the level of ERK activation in the nucleus was shown to balance proliferation (if nuclear ERK was high) versus differentiation (if nuclear ERK was low) in stem and progenitor cells [30]. Nuclear translocation of ERK is initiated by phosphorylation of its regulatory Tyr and Thr residues followed by exposure of the nuclear localization signal (NLS), subsequent phosphorylation by CKII, nuclear import through importin 7, and the regulation of up to 125 substrates (reviewed in [29]). Nuclear ERK substrates include transcription factors including c-MYC [31] and chromatin modifying enzymes, which makes it difficult to predict the functional consequence of repressed nuclear ERK activity in FGFR-SMO co-activated MB cells.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Neve

Migliavacca

Capdeville

et al. 2019

Cancers

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In the Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB), tumor initiation and progression are in part driven by smoothened (SMO) and fibroblast growth factor (FGF)-receptor (FGFR) signaling, respectively. We investigated the impact of the SMO-FGFR crosstalk on tumor growth and invasiveness in MB. We found that FGFR signaling represses GLI1 expression downstream of activated SMO in the SHH MB line DAOY and induces MKI67, HES1, and BMI1 in DAOY and in the group 3 MB line HD-MBO3. FGFR repression of GLI1 does not affect proliferation or viability, whereas inhibition of FGFR is necessary to release SMO-driven invasiveness. Conversely, SMO activation represses FGFR-driven sustained activation of nuclear ERK. Parallel activation of FGFR and SMO in ex vivo tumor cell-cerebellum slice co-cultures reduced invasion of tumor cells without affecting proliferation. In contrast, treatment of the cells with the SMO antagonist Sonidegib (LDE225) blocked invasion and proliferation in cerebellar slices. Thus, sustained, low-level SMO activation is necessary for proliferation and tissue invasion, whereas acute, pronounced activation of SMO can repress FGFR-driven invasiveness. This suggests that the tumor cell response is dependent on the relative local abundance of the two factors and indicates a paradigm of microenvironmental control of invasion in SHH MB through mutual control of SHH and FGFR signaling.

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“…Previous studies often focus on investigating the extent of ERK phosphorylation and its effect on transcription factors in the nucleus. However, ERK is known to have hundreds of substrates localized in different subcellular compartments and play key roles in differentiation, migration, and others (4,45,49). Despite our knowledge of substrate localization, little is known about the regulation of ERK in specific subcellular compartments outside of the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

Keyes

Ganesan

Molinar‐Inglis

et al. 2019

Preprint

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A variety of different signals induce specific responses through a common, ERK-dependent kinase cascade. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. 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. To address this question, we have expanded the toolbox of 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 enzymatic activity. 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 cytopolasm and nucleus. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. 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.

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Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

Cited by 158 publications

References 125 publications

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics

Novel insights into molecular mechanisms of Pseudourostyla cristata encystment using comparative transcriptomics

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

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