GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
| العنوان: | GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma |
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| المؤلفون: | Hui Fang Liang, Ze yang Ding, Qiu meng Liu, Jin Chen, Xiao long Tan, Jia Song, Deng Ning, Xuewu Zhang, Gan xun Li, Bi xiang Zhang, Jie Mo, Pengcheng Du, Qian yun Ge |
| المصدر: | Clinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021) Clinical and Translational Medicine |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Medicine (General), Carcinoma, Hepatocellular, Ubiquitin-Protein Ligases, TAK1, Medicine (miscellaneous), Protein degradation, Metastasis, Mitochondrial Proteins, R5-920, Ubiquitin, Downregulation and upregulation, Humans, Medicine, Neoplasm Metastasis, HCC, Protein kinase A, Research Articles, biology, Kinase, business.industry, Liver Neoplasms, Ubiquitination, MAP Kinase Kinase Kinases, Ubiquitin ligase, Repressor Proteins, GRAMD4, biology.protein, Cancer research, Molecular Medicine, business, Research Article, Signal Transduction, Transforming growth factor |
| الوصف: | Background Aberrant TAK1 (transforming growth factor β‐activated kinase 1) activity is known to be involved in a variety of malignancies, but the regulatory mechanisms of TAK1 remain poorly understood. GRAMD4 (glucosyltransferase Rab‐like GTPase activator and myotubularin domain containing 4) is a newly discovered p53‐independent proapoptotic protein with an unclear role in HCC (hepatocellular carcinoma). Results In this research, we found that GRAMD4 expression was lower in HCC samples, and its downregulation predicted worse prognosis for patients after surgical resection. Functionally, GRAMD4 inhibited HCC migration, invasion and metastasis. Mechanistically, GRAMD4 interacted with TAK1 to promote its protein degradation, thus, resulting in the inactivation of MAPK (Mitogen‐activated protein kinase) and NF‐κB pathways. Furthermore, GRAMD4 was proved to recruit ITCH (itchy E3 ubiquitin protein ligase) to promote the ubiquitination of TAK1. Moreover, high expression of TAK1 was correlated with low expression of GRAMD4 in HCC patients. Conclusions GRAMD4 inhibits the migration and metastasis of HCC, mainly by recruiting ITCH to promote the degradation of TAK1, which leads to the inactivation of MAPK and NF‐κB signalling pathways. We revealed a novel mechanism that GRAMD4 promotes the TAK1 ubiquitination and degradation by recruitment of ITCH, a E3 ubiquitin ligase of TAK1, which lead to the inhibition of MAPK and NF‐κB pathways and the downstream MMPs expression. |
| تدمد: | 2001-1326 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::92fd46b8807e4527e2f4b8345b54c49d https://doi.org/10.1002/ctm2.635 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....92fd46b8807e4527e2f4b8345b54c49d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20011326 |
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