ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer.
ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer.
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DOI：
10.15252/embr.202051182
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发表时间：
2022-02-03
期刊：
影响因子：
7.7
通讯作者：
Kasai K
中科院分区：
文献类型：
--
作者：
Tsunoda T;Riku M;Yamada N;Tsuchiya H;Tomita T;Suzuki M;Kizuki M;Inoko A;Ito H;Murotani K;Murakami H;Saeki Y;Kasai K
包括瘙痒在内的羟基型泛素E3连接酶通过泛素化多种底物来调节细胞功能的多个方面。众所周知，这些连接酶是变构自抑制的，需要激活蛋白来完全实现其底物的泛素化。在这里，我们证明了乳腺癌中下调的基因FAM189A2编码一种新型的瘙痒激活剂。FAM189A2是一种含有PPxY基序的跨膜蛋白，这些基序介导其与瘙痒的结合和泛素化。FAM189A2还与Epsin结合，并随着瘙痒在早期和晚期内吞体内蓄积。有趣的是，FAM189A2促进了趋化因子受体CXCR4与瘙痒的联系，并增强了瘙痒介导的CXCR4的泛素化。FAM189A2-基因敲除抑制CXCL12诱导的CXCR4的内吞作用，从而增强CXCL12对乳腺癌细胞的趋化和乳房形成的影响。与以往研究中已知的其他激活剂或适配器相比，FAM189A2是一种独特的针对瘙痒的激活剂，可以使CXCR4活性脱敏，我们建议将FAM189A2更名为内质体膜与EPsin的跨膜结合(Trep)。Strep是Hect型泛素E3连接酶瘙痒的激活剂，它介导趋化因子受体CXCR4的泛素化和内吞作用。STREP下调可减弱CXCR4的脱敏作用，从而促进乳腺癌的干性。
The HECT‐type ubiquitin E3 ligases including ITCH regulate many aspects of cellular function through ubiquitinating various substrates. These ligases are known to be allosterically autoinhibited and to require an activator protein to fully achieve the ubiquitination of their substrates. Here we demonstrate that FAM189A2, a downregulated gene in breast cancer, encodes a new type of ITCH activator. FAM189A2 is a transmembrane protein harboring PPxY motifs, and the motifs mediate its association with and ubiquitination by ITCH. FAM189A2 also associates with Epsin and accumulates in early and late endosomes along with ITCH. Intriguingly, FAM189A2 facilitates the association of a chemokine receptor CXCR4 with ITCH and enhances ITCH‐mediated ubiquitination of CXCR4. FAM189A2‐knockout prohibits CXCL12‐induced endocytosis of CXCR4, thereby enhancing the effects of CXCL12 on the chemotaxis and mammosphere formation of breast cancer cells. In comparison to other activators or adaptors known in the previous studies, FAM189A2 is a unique activator for ITCH to desensitize CXCR4 activity, and we here propose that FAM189A2 be renamed as ENdosomal TRansmembrane binding with EPsin (ENTREP). ENTREP is an activator for HECT‐type ubiquitin E3 ligase ITCH, which mediates ubiquitination and endocytosis of a chemokine receptor CXCR4. ENTREP downregulation attenuates CXCR4 desensitization, thereby promoting breast cancer stemness.
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影响因子：
14.9
作者：
Dobson L;Reményi I;Tusnády GE
通讯作者：
Tusnády GE
影响因子：
--
作者：
Inaguma S;Riku M;Ito H;Tsunoda T;Ikeda H;Kasai K
通讯作者：
Kasai K
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
--
作者：
Garrone NF;Blazer-Yost BL;Weiss RB;Lalouel JM;Rohrwasser A
通讯作者：
Rohrwasser A
DOI：
10.1016/bs.pmbts.2015.02.005
发表时间：
2015
影响因子：
--
作者：
Kennedy JE;Marchese A
通讯作者：
Marchese A