RAS Dimers: The Novice Couple at the RAS-ERK Pathway Ball

Herrero, Ana; Crespo, Piero

doi:10.3390/genes12101556

Cited by 10 publications

(8 citation statements)

References 91 publications

(168 reference statements)

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“…Although MAPKs were shown to exert their function at cytoplasmic as well as nuclear cellular compartments ( Figure 1 ), the latter is probably the most widely studied and several functions have been described including regulation of transcription, DNA replication, chromatin remodeling, and miRNA synthesis. Regulatory components, such as scaffold proteins and dimerization were shown to take part in this pathway’s complex regulation by defining frequency, amplitude and intensity of the signal allowing for a wide range of biological outcomes ( Herrero and Crespo, 2021 ). Several reports suggest that ERK nuclear localization depends, among others, on ERK expression levels such that overexpression increases nuclear translocation probability by passive diffusion ( Fukuda et al, 1997 ), and phosphorylation by casein kinase 2 (CK2) that enhances ERK interaction with a nuclear import protein (importin 7) ( Chuderland et al, 2008 ).…”

Section: Upon Extracellular-signal Regulated Kinase Activationmentioning

confidence: 99%

Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace

Ramos

Feld

Fustiñana

2022

Front. Mol. Neurosci.

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The ability to learn from experience and consequently adapt our behavior is one of the most fundamental capacities enabled by complex and plastic nervous systems. Next to cellular and systems-level changes, learning and memory formation crucially depends on molecular signaling mechanisms. In particular, the extracellular-signal regulated kinase 1/2 (ERK), historically studied in the context of tumor growth and proliferation, has been shown to affect synaptic transmission, regulation of neuronal gene expression and protein synthesis leading to structural synaptic changes. However, to what extent the effects of ERK are specifically related to memory formation and stabilization, or merely the result of general neuronal activation, remains unknown. Here, we review the signals leading to ERK activation in the nervous system, the subcellular ERK targets associated with learning-related plasticity, and how neurons with activated ERK signaling may contribute to the formation of the memory trace.

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Section: Upon Extracellular-signal Regulated Kinase Activationmentioning

confidence: 99%

Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace

Ramos

Feld

Fustiñana

2022

Front. Mol. Neurosci.

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“…This comprises a three-tiered signaling module sequentially linking MAPKKKs of the RAF family serine/threonine kinases (ARAF, BRAF and CRAF); MAPKKs dual-specificity kinases MEK 1 and 2; and MAPKs ERK 1 and 2, in a cascade of serial phosphorylation events, whereby the kinases at the different tiers are consecutively activated. Noticeably, data accumulated over two decades reveal that most of the constituents of the RAS–ERK pathway are capable of forming higher-order assemblies, particularly dimers [ 55 ]. As the last step in the cascade, once phosphorylated/activated, ERKs ultimately convey signals to an ample repertoire of substrates, localized at different subcellular localizations, which eventually translate the biochemical signal into the regulation of key cellular processes such as proliferation, differentiation, survival and motility, in addition to a wide variety of cell-specific activities [ 56 , 57 ].…”

Section: The Ras–erk Pathwaymentioning

confidence: 99%

Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma

et al. 2022

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Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS–ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.

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“…The RAS-ERK pathway exerts a significant function when adjusting pivotal cellular activities, covering proliferation, survival, differentiation, and motility, and is a cascade that translates the extracellular environment into intracellular signaling, encompassing a range of biochemical processes [12,13]. It has been suggested that the biological effects of GTPase activator protein 1 (IQGAP1) on tumor cells can be induced by regulating the response of the RAS signaling pathway [14] and binding to actin is contained in diverse processes like cell binding, propagation, circulate, and transfer [15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

IPO5 Mediates EMT and Promotes Esophageal Cancer Development through the RAS-ERK Pathway

Li¹,

Li²,

Chen³

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. In the development of many tumors, IPO5, as a member of the nuclear transporter family, exerts a significant function. Also, IPO5 is used as a therapeutic target for tumors based on some reports. By studying IPO5 expression in esophageal cancer tissues, the mechanism associated with IPO5 improving esophageal cancer development was explored in this study. Methods. To gain differentially expressed genes, this study utilized mRNA microarray and TCGA database for comprehensive analysis of esophageal cancer tissues and normal esophageal cancer tissues, and then the differentially expressed gene IPO5 was screened by us. To assess esophageal cancer patients’ prognosis, this study also applied the Kaplan-Meier analysis, and we also conducted the GSEA enrichment analysis to investigate IPO5-related signaling pathways. This study performed TISIDB and TIMER online analysis tools to study the correlation between IPO5 and immune regulation and infiltration. We took specimens of esophageal cancer from patients and detected the expression of IPO5 in tumor and normal tissues by immunohistochemistry. The IPO5 gene-silenced esophageal cancer cell model was constructed by lentivirus transfection. Through the Transwell invasion assay, CCK-8 assay, and cell scratch assay, this study investigated the effects of IPO5 on cell propagation, invasion, and transfer. What is more, we identified the influences of IPO5 on the cell cycle through flow cytometry and established a subcutaneous tumor-forming model in nude mice. Immunohistochemistry was used to verify the expression of KI-67, and this study detected the modifications of cell pathway-related proteins using Western blot and applied EMT-related proteins to explain the mechanism of esophageal cancer induced by IPO5. Results. According to database survival analysis, IPO5 high-expression patients had shorter disease-free survival than IPO5 low-expression patients. Compared to normal tissues, the IPO5 expression in cancer tissues was significantly higher in clinical trials ( P < 0.05 ). Through TISIDB and TIMER database studies, we found that IPO5 could affect immune regulation, and the age of IPO5 expression grows with the increase of immune infiltration level. The IPO5 expression in esophageal cancer cells was higher than normal, especially in ECA109 and OE33 cells ( P < 0.01 ). After knocking out IPO5 gene expression, cell proliferation capacity and invasion capacity were reduced ( P < 0.05 ) and decreased ( P < 0.01 ) in the IPO5-interfered group rather than the negative control group. The growth cycle of esophageal carcinoma cells was arrested in the G2/M phase after IPO5 gene silencing ( P < 0.01 ). Tumor-forming experiments in nude mice confirmed that after IPO5 deletion, the tumor shrank, the expression of KI67 decreased, the downstream protein expression level of the RAS pathway decreased after sh-IPO5 interference ( P < 0.01 ), and the level of EMT marker delined ( P < 0.05 ). Conclusion. In esophageal cancer, IPO5 is highly expressed and correlates with survival rate. Esophageal cancer cell growth and migration were significantly affected by the inhibition of IPO5 in vitro and in vivo. IPO5 mediates EMT using the RAS-ERK signaling pathway activation and promotes esophageal cancer cell development in vivo and in vitro.

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RAS Dimers: The Novice Couple at the RAS-ERK Pathway Ball

Cited by 10 publications

References 91 publications

Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace

Contributions of extracellular-signal regulated kinase 1/2 activity to the memory trace

Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma

IPO5 Mediates EMT and Promotes Esophageal Cancer Development through the RAS-ERK Pathway

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