ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling.
ISGylation drives basal breast tumour progression by promoting EGFR recycling and Akt signalling.
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DOI：
10.1038/s41388-021-02017-8
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发表时间：
2021-11
期刊：
影响因子：
8
通讯作者：
von Kriegsheim A
中科院分区：
文献类型：
--
作者：
Bolado-Carrancio A;Lee M;Ewing A;Muir M;Macleod KG;Gallagher WM;Nguyen LK;Carragher NO;Semple CA;Brunton VG;Caswell PT;von Kriegsheim A
ISG 15是一种与乳腺癌患者生存率降低相关的泛素样修饰物。然而，ISG 15实现这一目标的机制仍然难以捉摸。我们证明了通过ISG 15（ISGylation）修饰Rab GDP-解离抑制剂β（GDI 2）改变了使用ISGylation的CRISPR敲除模型在非干扰素刺激的细胞中EGF受体（EGFR）的内吞再循环。通过调节EGFR运输，ISGylation增强EGFR再循环并维持Akt信号传导。我们进一步表明，Akt信号传导与基底乳腺癌队列中ISG 15及其E2连接酶的水平呈正相关，证实了人类肿瘤中ISGylation和Akt信号传导之间的联系。持续和增强的Akt激活解释了在人类乳腺癌中观察到的更具侵略性的肿瘤行为。我们发现ISGylation可以作为肿瘤进展的驱动因素，而不仅仅是旁观者。
ISG15 is an ubiquitin-like modifier that is associated with reduced survival rates in breast cancer patients. The mechanism by which ISG15 achieves this however remains elusive. We demonstrate that modification of Rab GDP-Dissociation Inhibitor Beta (GDI2) by ISG15 (ISGylation) alters endocytic recycling of the EGF receptor (EGFR) in non-interferon stimulated cells using CRISPR-knock out models for ISGylation. By regulating EGFR trafficking, ISGylation enhances EGFR recycling and sustains Akt-signalling. We further show that Akt signalling positively correlates with levels of ISG15 and its E2-ligase in basal breast cancer cohorts, confirming the link between ISGylation and Akt signalling in human tumours. Persistent and enhanced Akt activation explains the more aggressive tumour behaviour observed in human breast cancers. We show that ISGylation can act as a driver of tumour progression rather than merely being a bystander.
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影响因子：
64.5
作者：
Boelens MC;Wu TJ;Nabet BY;Xu B;Qiu Y;Yoon T;Azzam DJ;Twyman-Saint Victor C;Wiemann BZ;Ishwaran H;Ter Brugge PJ;Jonkers J;Slingerland J;Minn AJ
通讯作者：
Minn AJ
影响因子：
8
作者：
Kiessling, A.;Hogrefe, C.;Seliger, B.
通讯作者：
Seliger, B.
影响因子：
11.8
作者：
Cerikan, Berati;Shaheen, Ranad;Schiebel, Elmar
通讯作者：
Schiebel, Elmar
影响因子：
2.7
作者：
Ankney, J. Astor;Xie, Ling;Chen, Xian
通讯作者：
Chen, Xian
DOI：
10.1016/j.bbrc.2005.08.132
发表时间：
2005-10-21
影响因子：
3.1
作者：
Giannakopoulos, NV;Luo, JK;Zhang, DE
通讯作者：
Zhang, DE