GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	GRAMD4 HCC Metastasis TAK1 Ubiquitination Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/53eba7c6cc954f4fae0d49a14cfacd22
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spelling	oai:doaj.org-article:53eba7c6cc954f4fae0d49a14cfacd222021-11-30T07:25:38ZGRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma2001-132610.1002/ctm2.635https://doaj.org/article/53eba7c6cc954f4fae0d49a14cfacd222021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.635https://doaj.org/toc/2001-1326Abstract 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.Qian yun GeJin ChenGan xun LiXiao long TanJia SongDeng NingJie MoPeng cheng DuQiu meng LiuHui fang LiangZe yang DingXue wu ZhangBi xiang ZhangWileyarticleGRAMD4HCCMetastasisTAK1UbiquitinationMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GRAMD4 HCC Metastasis TAK1 Ubiquitination Medicine (General) R5-920
spellingShingle	GRAMD4 HCC Metastasis TAK1 Ubiquitination Medicine (General) R5-920 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 GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
description	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.
format	article
author	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
author_facet	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
author_sort	Qian yun Ge
title	GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
title_short	GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
title_full	GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
title_fullStr	GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
title_full_unstemmed	GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma
title_sort	gramd4 inhibits tumour metastasis by recruiting the e3 ligase itch to target tak1 for degradation in hepatocellular carcinoma
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/53eba7c6cc954f4fae0d49a14cfacd22
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GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma

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