GRAMD4 Inhibits Tumour Metastasis by Recruiting the E3 Ligase ITCH to Target TAK1 for Degradation in Hepatocellular Carcinoma

Overview

Journal Clin Transl Med

Publisher Wiley

Specialty General Medicine

Date 2021 Nov 29

PMID 34841685

Citations 7

Authors

Qian Yun Ge

Jin Chen

Gan Xun Li

Xiao Long Tan

Jia Song

Deng Ning

Jie Mo

Peng Cheng Du

Qiu Meng Liu

Hui Fang Liang

Ze Yang Ding

Xue Wu Zhang

Bi Xiang Zhang

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Su W, Gao W, Zhang R, Wang Q, Li L, Bu Q JHEP Rep. 2023; 5(5):100695.

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