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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-11-01
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| Series: | Clinical and Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ctm2.635 |
| _version_ | 1818997642072424448 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T21:48:52Z |
| format | Article |
| id | doaj.art-53eba7c6cc954f4fae0d49a14cfacd22 |
| institution | Directory Open Access Journal |
| issn | 2001-1326 |
| language | English |
| last_indexed | 2024-12-20T21:48:52Z |
| publishDate | 2021-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj.art-53eba7c6cc954f4fae0d49a14cfacd222022-12-21T19:25:36ZengWileyClinical and Translational Medicine2001-13262021-11-011111n/an/a10.1002/ctm2.635GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinomaQian yun Ge0Jin Chen1Gan xun Li2Xiao long Tan3Jia Song4Deng Ning5Jie Mo6Peng cheng Du7Qiu meng Liu8Hui fang Liang9Ze yang Ding10Xue wu Zhang11Bi xiang Zhang12Hepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaHepatic Surgery Center Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan P. R. ChinaAbstract 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.https://doi.org/10.1002/ctm2.635GRAMD4HCCMetastasisTAK1Ubiquitination |
| spellingShingle | 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 Clinical and Translational Medicine GRAMD4 HCC Metastasis TAK1 Ubiquitination |
| title | 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_short | 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 |
| topic | GRAMD4 HCC Metastasis TAK1 Ubiquitination |
| url | https://doi.org/10.1002/ctm2.635 |
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