ArticleNature communications2019
K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 89 citations in OpenAlex.
- ZG16 represses tumor progression and M2 polarization of tumor-associated macrophages in hepatocellular carcinoma by promoting ubiquitination and degradation of SNX9 via binding to ITCH.Hepatology international · 2026Article
- Highly specific intracellular ubiquitination of a small molecule.Nature chemical biology · 2026Article
- GCN5-ERK lactylation-phosphorylation loop amplifies lactate-driven cancer progression.Nature chemical biology · 2026Article
- The Crosstalk Between CRL5 and APC/C E3 Ligases Regulates Metastasis and Chemosensitivity of Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- The Ubiquitin Script: writing protein fates in chains.Essays in biochemistry · 2025Review
- Lactylation-driven USP4-mediated ANXA2 stabilization and activation promotes maintenance and radioresistance of glioblastoma stem cells.Cell death and differentiation · 2025Article
- E3 ligase TRIM22 promotes melanoma proliferation by regulating cell cycle progression through K63-linked ubiquitination of p21.Scientific reports · 2025Article
- Linear ubiquitination of p31Cell & bioscience · 2025Article
- TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas.Neuro-oncology · 2025Article
- K27-linked RORγt ubiquitination by Nedd4 potentiates Th17-mediated autoimmunity.Journal of biomedical science · 2025Article
- The mTOR pathway controls phosphorylation of BRAF at T401.Cell communication and signaling : CCS · 2024Article
- Integrated single-cell and spatial transcriptomic analysis reveals YBX1 drives immune regulation in GBM progression.Heliyon · 2024Article
- Myofibrillogenesis Regulator-1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin-Protein Ligase Itchy Homolog in the Metastasis of Non-Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- RNF43 Inactivation Enhances the B-RAF/MEK Signaling and Creates a Combinatory Therapeutic Target in Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis.Cell death & disease · 2024Article
- Synergistic inhibition of NUDT21 by secretory S100A11 and exosomal miR-487a-5p promotes melanoma oligo- to poly-metastatic progression.Molecular oncology · 2023Article
- ITCH-Mediated Ubiquitylation of ITGB3 Promotes Cell Proliferation and Invasion of Ectopic Endometrial Stromal Cells in Ovarian Endometriosis.Biomedicines · 2023Article
- Ubiquitination detection techniques.Experimental biology and medicine (Maywood, N.J.) · 2023Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
Abstract
BRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated BRAF activation have been extensively characterized, however, it remains undefined how BRAF function is fine-tuned by stimuli other than growth factors. Here, we report that in response to proinflammatory cytokines, BRAF is subjected to lysine 27-linked poly-ubiquitination in melanoma cells by the ITCH ubiquitin E3 ligase. Lysine 27-linked ubiquitination of BRAF recruits PP2A to antagonize the S365 phosphorylation and disrupts the inhibitory interaction with 14-3-3, leading to sustained BRAF activation and subsequent elevation of the MEK/ERK signaling. Physiologically, proinflammatory cytokines activate ITCH to maintain BRAF activity and to promote proliferation and invasion of melanoma cells, whereas the ubiquitination-deficient BRAF mutant displays compromised kinase activity and reduced tumorigenicity. Collectively, our study reveals a pivotal role for ITCH-mediated BRAF ubiquitination in coordinating the signals between cytokines and the MAPK pathway activation in melanoma cells.
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Registered trials
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.