The E3 ligase TRAF4 promotes IGF signaling by mediating atypical ubiquitination of IRS-1
| Autor: | Bert W. O'Malley, Zhao Wang, Ping Yi, Ramesh Singh, Wenjuan Yu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
IGFR insulin-like growth factor receptor IGF insulin-like growth factor medicine.medical_treatment proliferation PTB phosphotyrosine binding Insulin-Like Growth Factor Receptor Biochemistry 03 medical and health sciences Insulin-like growth factor chemistry.chemical_compound Insulin receptor substrate medicine Humans Insulin-Like Growth Factor I Molecular Biology Protein kinase B TNF receptor associated factor (TRAF) Insulin-like growth factor 1 receptor TNF Receptor-Associated Factor 4 030102 biochemistry & molecular biology biology co-IP coimmunoprecipitation Akt insulin receptor substrate 1 (IRS-1) Ubiquitination Tyrosine phosphorylation Cell Biology insulin-like growth factor (IGF) Ubiquitin ligase Cell biology protein phosphorylation 030104 developmental biology HEK293 Cells chemistry biology.protein IRS insulin receptor substrate Insulin Receptor Substrate Proteins MCF-7 Cells Signal transduction Research Article HA hemagglutinin Signal Transduction |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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