ArticleGenes & development2017
Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs.
Article in Genes & development, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 61 citations in OpenAlex.
- The Protein Phosphatase Inhibitor LB100 Targets the Mesenchymal Lineage of Pancreatic Ductal Adenocarcinoma.MedComm · 2026Article
- RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway.iScience · 2026Article
- Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing.bioRxiv : the preprint server for biology · 2026Article
- Integrator 20th anniversary: a molecular machine indispensable in development and disease.Trends in molecular medicine · 2026Review
- Ganglioside GM2 induces epithelial-mesenchymal transition (EMT) in cancer cells in a MEK/ERK/Egr1-dependent transcriptional program.The Journal of biological chemistry · 2026Article
- Integrator promotes the association of TFIID and RNA polymerase II to maintain pluripotency during development.Molecular cell · 2025Article
- Integrator complex subunit 12 knockout overcomes a transcriptional block to HIV latency reversal.eLife · 2025Article
- NOTCH, ERK, and SHH signaling respectively control the fate determination of cortical glia and olfactory bulb interneurons.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Fateful Decisions of Where to Cut the Line: Pathology Associated with Aberrant 3' End Processing and Transcription Termination.Journal of molecular biology · 2025Review
- Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The Integrator complex: an emerging complex structure involved in the regulation of gene expression by targeting RNA polymerase II.Functional & integrative genomics · 2024Review
- PTPN2 copper-sensing relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression.Nature communications · 2024Article
- Transcription directionality is licensed by Integrator at active human promoters.Nature structural & molecular biology · 2024Article
- AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells.Molecular cancer research : MCR · 2023Article
- Genomic regulation of transcription and RNA processing by the multitasking Integrator complex.Nature reviews. Molecular cell biology · 2023Review
- The Integrator complex regulates microRNA abundance through RISC loading.Science advances · 2023Article
- Integrator is a global promoter-proximal termination complex.Molecular cell · 2023Review
- SUMO conjugation regulates the activity of the Integrator complex.Nucleic acids research · 2022Article
- Integrator endonuclease drives promoter-proximal termination at all RNA polymerase II-transcribed loci.Molecular cell · 2022Article
- Comparative whole-genome transcriptome analysis in renal cell populations reveals high tissue specificity of MAPK/ERK targets in embryonic kidney.BMC biology · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Activating mutations in the mitogen-activated protein kinase (MAPK) cascade, also known as the RAS-MEK-extracellular signal-related kinase (ERK1/2) pathway, are an underlying cause of >70% of human cancers. While great strides have been made toward elucidating the cytoplasmic components of MAPK signaling, the key downstream coactivators that coordinate the transcriptional response have not been fully illustrated. Here, we demonstrate that the MAPK transcriptional response in human cells is funneled through Integrator, an RNA polymerase II-associated complex. Integrator depletion diminishes ERK1/2 transcriptional responsiveness and cellular growth in human cancers harboring activating mutations in MAPK signaling. Pharmacological inhibition of the MAPK pathway abrogates the stimulus-dependent recruitment of Integrator at immediate early genes and their enhancers. Following epidermal growth factor (EGF) stimulation, activated ERK1/2 is recruited to immediate early genes and phosphorylates INTS11, the catalytic subunit of Integrator. Importantly, in contrast to the broad effects of Integrator knockdown on MAPK responsiveness, depletion of a number of critical subunits of the coactivator complex Mediator alters only a few MAPK-responsive genes. Finally, human cancers with activating mutations in the MAPK cascade, rendered resistant to targeted therapies, display diminished growth following depletion of Integrator. We propose Integrator as a crucial transcriptional coactivator in MAPK signaling, which could serve as a downstream therapeutic target for cancer treatment.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.