ArticleThe Journal of biological chemistry
The E3 ligase TRAF4 promotes IGF signaling by mediating atypical ubiquitination of IRS-1.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- Lnc-EST885 promotes hepatocellular carcinoma metastasis through PI3K / AKT pathway by interaction with TRAF4.Translational oncology · 2025Article
- Research progress on the association of insulin resistance with type 2 diabetes mellitus and Alzheimer's disease.Metabolic brain disease · 2024Review
- Neddylation of insulin receptor substrate acts as a bona fide regulator of insulin signaling and its implications for cancer cell migration.Cancer gene therapy · 2024Article
- Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila.Nature communications · 2024Article
- Advancing Breast Cancer Therapeutics: Targeted Gene Delivery Systems Unveiling the Potential of Estrogen Receptor-Targeting Ligands.Biomaterials research · 2024Article
- TRAF4-mediated nonproteolytic ubiquitination of androgen receptor promotes castration-resistant prostate cancer.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The role of microRNA-4723-5p regulated by c-myc in triple-negative breast cancer.Bioengineered · 2022Article
- The Research Progress in Physiological and Pathological Functions of TRAF4.Frontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Insulin-like growth factor (IGF) is a potent mitogen that activates the IGF receptor (IGFR)/insulin receptor substrate (IRS) axis, thus stimulating growth in normal cells and uncontrolled cell proliferation in cancer. Posttranslational modifications of IRS such as ubiquitination tightly control IGF signaling, and we previously identified IRS-1 as a potential substrate for the E3 ubiquitin ligase TRAF4 using an unbiased screen. Here we provide evidence that TRAF4-mediated ubiquitination of IRS-1 is physiologically relevant and crucial for IGF signal transduction. Through site-directed mutagenesis we found that TRAF4 promotes an atypical K29-linked ubiquitination at the C-terminal end of IRS-1. Its depletion abolishes AKT and ERK phosphorylation downstream of IGF-1 and inhibits breast cancer cell proliferation. Overexpression of TRAF4 enhances IGF1-induced IGFR-IRS-1 interaction, IRS-1 tyrosine phosphorylation, and downstream effector protein activation, whereas mutation of IRS-1 ubiquitination sites completely abolishes these effects. Altogether, our studies demonstrate that nonproteolytic ubiquitination of IRS-1 is a key step in conveying IGF-1 stimulation from IGFR to IRS-1.
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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.