GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma.
GRAMD4 inhibits tumour metastasis by recruiting the E3 ligase ITCH to target TAK1 for degradation in hepatocellular carcinoma.
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GRAMD4 通过招募 E3 连接酶 ITCH 来靶向 TAK1 以降解肝细胞癌，从而抑制肿瘤转移。
DOI：
10.1002/ctm2.635
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发表时间：
2021-11
影响因子：
10.6
通讯作者：
Zhang BX
中科院分区：
文献类型：
--
作者：
Ge QY;Chen J;Li GX;Tan XL;Song J;Ning D;Mo J;Du PC;Liu QM;Liang HF;Ding ZY;Zhang XW;Zhang BX
转化生长因子活化蛋白1(Transform Growth For Growth Forβ-Actiated Kinase 1，TAK1)活性异常与多种恶性肿瘤有关，但其调控机制尚不清楚。GRAMD4(葡萄糖基转移酶Rab样GTPase激活物和肌管蛋白结构域包含4)是新近发现的一种不依赖于p53的促凋亡蛋白，但在肝细胞癌中的作用尚不清楚。在这项研究中，我们发现GRAMD4在肝癌组织中的表达较低，其下调预示着手术切除后患者的预后较差。GRAMD4在功能上抑制了肝癌的迁移、侵袭和转移。在机制上，GRAMD4与Tak1相互作用，促进其蛋白质降解，从而导致丝裂原活化蛋白激酶(MAPK)和NF-κB途径失活。此外，GRAMD4被证明招募瘙痒(瘙痒的E3泛素蛋白连接酶)来促进TAK1的泛素化。此外，在肝癌患者中，TAK1的高表达与GRAMD4的低表达相关。GRAMD4抑制肝癌细胞的迁移和转移，主要是通过募集ITCH来促进Tak1的降解，从而导致MAPK和NF-κB信号通路的失活。我们揭示了一种新的机制，即GRAMD4通过募集Tak1的E3泛素连接酶ITCH来促进Tak1的泛素化和降解，从而抑制MAPK和NF-κB途径以及下游MMPs的表达。
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). 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. 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.
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