SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF.
SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF.
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SPOP 通过促进 BRAF 的非降解性泛素化抑制 BRAF 依赖性肿瘤发生
DOI：
10.1186/s13578-022-00950-z
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发表时间：
2022-12-30
影响因子：
7.5
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Feng, Kai;Shi, Qing;Jiao, Dongyue;Chen, Yingji;Yang, Wanqi;Su, Ke;Wang, Yalan;Huang, Yan;Zhang, Pingzhao;Li, Yao;Wang, Chenji
编码E3泛素连接酶底物结合衔接子斑点型BTB/POZ蛋白（SPOP）的基因在前列腺癌（PCa）和子宫内膜癌（EC）中经常发生突变;然而，SPOP突变对肿瘤发生的分子机制仍然知之甚少。BRAF具有潜在的SPOP结合共有基序（SBC）基序。免疫共沉淀试验证明BRAF与SPOP相互作用。在细胞系中进行了一系列功能分析，以研究SPOP突变引起的MAPK/ERK激活的生物学意义。细胞质SPOP结合并诱导BRAF的非降解性泛素化，从而减少BRAF与MAPK/ERK途径的其他核心组分之间的相互作用。SPOP消融增加MAPK/ERK激活。EC-或PCa-相关的SPOP突变体表现出降低的能力，结合和泛素化BRAF。此外，癌症相关的BRAF突变破坏了BRAF-SPOP相互作用，并允许BRAF逃避SPOP介导的泛素化，从而上调MAPK/ERK信号传导并增强癌细胞的肿瘤表型。我们的发现为SPOP突变驱动的肿瘤发生和MAPK/ERK通路的异常BRAF依赖性激活之间的分子联系提供了新的见解。在线版本包含补充材料，可通过10.1186/s13578-022-00950-z获得。
The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. The online version contains supplementary material available at 10.1186/s13578-022-00950-z.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
3.3
作者：
Heunis T;Lamoliatte F;Marín-Rubio JL;Dannoura A;Trost M
通讯作者：
Trost M
SPOP 突变前列腺癌中 INF2 介导的线粒体分裂失调
影响因子：
4.5
作者：
Jin, Xiaofeng;Wang, Jie;Wang, Chenji
通讯作者：
Wang, Chenji
影响因子：
8
作者：
Li, C.;Ao, J.;Fu, J.;Lee, D-F;Xu, J.;Lonard, D.;O'Malley, B. W.
通讯作者：
O'Malley, B. W.
影响因子：
30.8
作者：
Le Gallo, Matthieu;O'Hara, Andrea J.;Rudd, Meghan L.;Urick, Mary Ellen;Hansen, Nancy F.;O'Neil, Nigel J.;Price, Jessica C.;Zhang, Suiyuan;England, Bryant M.;Godwin, Andrew K.;Sgroi, Dennis C.;Hieter, Philip;Mullikin, James C.;Merino, Maria J.;Bell, Daphne W.
通讯作者：
Bell, Daphne W.