ArticleOncogene2013
Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition.
Article in Oncogene, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 90 citations in OpenAlex.
- Dual-specificity protein phosphatase DUSP4 regulates response to MEK inhibition in BRAF wild-type melanoma.British journal of cancer · 2020Trial
- Protease-Activated Receptor-2 as a Proteolytic Rheostat in Colorectal and Pancreatic Cancer: From Mechanism to Biomarker-Guided Therapy.International journal of molecular sciences · 2026Review
- Novel Exploratory Transcriptomic Candidates as Biomarkers and Cancer Hallmark Fingerprints for Ovarian Endometroid and Clear Cell Carcinomas in Women.Antioxidants (Basel, Switzerland) · 2026Article
- RRAS and RRAS2 Mutations Are Recurrent Oncogenic Drivers in Lung Cancer and Are Sensitive to the Pan-RAS Inhibitor RMC-6236.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- MEK5/ERK5 inhibition sensitizes NRAS-mutant melanoma to MAPK-targeted therapy by preventing Cyclin D/CDK4-mediated G1/S progression.Cell death & disease · 2025Article
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- Reporter-based screening identifies RAS-RAF mutations as drivers of resistance to active-state RAS inhibitors in colorectal cancer.Science signaling · 2025Article
- The interplay between COX-2, chemotherapeutic drugs, and chemoresistance in colon cancer.Scientific reports · 2025Article
- Integrative Computational Framework,bioRxiv : the preprint server for biology · 2024Article
- KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways.Cells · 2024Review
- Calcium-Dependent Regulation of Neuronal Excitability Is Rescued in Fragile X Syndrome by a Tat-Conjugated N-Terminal Fragment of FMRP.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Identifying the tumor location-associated candidate genes in development of new drugs for colorectal cancer using machine-learning-based approach.Medical & biological engineering & computing · 2022Article
- Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification.International journal of molecular sciences · 2022Article
- DUSP4 protects BRAF- and NRAS-mutant melanoma from oncogene overdose through modulation of MITF.Life science alliance · 2022Article
- SuperDendrix algorithm integrates genetic dependencies and genomic alterations across pathways and cancer types.Cell genomics · 2022Article
- PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells.Gut · 2022Article
- Article
- The MEK/ERK Network as a Therapeutic Target in Human Cancer.Molecular cancer research : MCR · 2021Review
- Distinct JNK/VEGFR signaling on angiogenesis of breast cancer-associated pleural fluid based on hormone receptor status.Cancer science · 2021Article
- Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion.Neoplasia (New York, N.Y.) · 2020Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Gain-of-function mutations in KRAS and BRAF genes are found in up to 50% of colorectal cancers. These mutations result in the activation of the BRAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogen-activated protein kinases. Upon activation, ERK1/2 translocate from the cytoplasm to the nucleus. This process has been shown to be required for the induction of many cellular responses, although the molecular mechanisms regulating ERK nuclear function, especially under oncogenic stimulation, remain to be explored. Herein, we examined the spatiotemporal regulation of ERK1/2 activity upon oncogenic activation of KRAS(G12V) and BRAF(V600E) in normal intestinal epithelial crypt cells (IECs). Results demonstrate that expression of these oncogenes markedly stimulated ERK1/2 activities and morphologically transformed IECs. Importantly however, ERK phosphorylation was not observed in the nucleus, but restricted to the cytoplasm of KRAS(G12V)- and BRAF(V600E)-transformed IECs. The absence of nuclear ERK phosphorylation was due to a vanadate-sensitive phosphatase activity. Nuclear ERK dephosphorylation was found to be tightly correlated with the rapid expression of DUSP4 phosphatase induced in an MEK-dependent manner. In addition, MEK-dependent phosphorylation of T361, T363, S390 and S395 residues highly stabilized DUSP4 protein. Finally, in human colorectal cancer cells, ERK1/2 activities were also confined to the cytoplasm and treatment with pervanadate reactivated ERK1/2 in the nucleus. Accordingly, DUSP4 mRNAs were found to be highly expressed, in an MEK-dependent manner, in all colorectal cancer cells analyzed. These findings indicate that DUSP4 functions as part of a negative feedback mechanism in the control of the duration and magnitude of nuclear ERK activation during intestinal tumorigenesis.
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