详情页 - 聚合机构库演示平台

当前位置：首页 > 详情页

Aberrant phosphorylation of SMAD4 Thr277-mediated USP9x-SMAD4 interaction by free fatty acids promotes breast cancer metastasis

文献详情

资源类型：

Pubmed体系：

收录情况： ◇ 自然指数

作者：

单位： [a]Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90059, United States [b]David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, United States [c]Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China [d]Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China

出处：

DOI：

ISSN：

摘要：

Obesity increases the risk of distant metastatic recurrence and reduces breast cancer survival. However, the mechanisms behind this pathology and identification of relevant therapeutic targets are poorly defined. Plasma free fatty acids (FFA) levels are elevated in obese individuals. Here we report that TGFβ transiently activates ERK and subsequently phosphorylates SMAD4 at Thr277, which facilitates a SMAD4-USP9x interaction, SMAD4 nuclear retention, and stimulates TGFβ/SMAD3- mediated transcription of Twist and Snail. USP9x inhibited the E3 ubiquitin-protein ligase TIF1γ from binding and monoubiquitinating SMAD4, hence maintaining the SMAD4 nuclear retention. FFA further facilitated TGFβ-induced ERK activation, SMAD4 phosphorylation, and nuclear retention, promoting TGFβ-dependent cancer progression. Inhibition of ERK and USP9x suppressed obesity-induced metastasis. In addition, clinical data indicated that phospho-ERK and -SMAD4 levels correlate with activated TGFb signaling and metastasis in overweight/ obese patient breast cancer specimens. Altogether, we demonstrate the vital interaction of USP9x and SMAD4 for governing TGFβ signaling and dyslipidemia-induced aberrant TGFβ activation during breast cancer metastasis. © 2017 American Association for Cancer Research.

语种：

PubmedID：

中科院(CAS)分区：

出版当年[2016]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区肿瘤学

第一作者：

第一作者单位： [a]Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90059, United States [b]David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, United States

通讯作者：

通讯机构： [a]Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90059, United States [b]David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, United States

推荐引用方式(GB/T 7714)：

APA：

MLA：