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学科主题: 临床医学
题名:
SchA-p85-FAK complex dictates isoform-specific activation of Akt2 and subsequent PCBP1-mediated post-transcriptional regulation of TGF beta-mediated epithelial to mesenchymal transition in human lung cancer cell line A549
作者: Xue, Xinying1,6; Wang, Xin7; Liu, Yuxia2,3; Teng, Guigen4; Wang, Yong1; Zang, Xuefeng5; Wang, Kaifei6; Zhang, Jinghui1; Xu, Yali1; Wang, Jianxin6; Pan, Lei1
关键词: Lung cancer ; EMT ; TGF-beta ; PCBP1 ; ILEI ; Dab2 ; Akt2
刊名: TUMOR BIOLOGY
发表日期: 2014-08-01
DOI: 10.1007/s13277-014-1982-1
卷: 35, 期:8, 页:7853-7859
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: PROTEINS ; SHC ; IDENTIFICATION ; RESIDUES ; RECEPTOR ; SUBUNIT ; BINDING ; P85
英文摘要:

A post-transcriptional pathway by which TGF-beta modulates expression of specific proteins, Disabled-2 (Dab2) and Interleukin-like EMT Inducer (ILEI), inherent to epithelial to mesenchymal transition (EMT) in murine epithelial cells through Akt2-mediated phosphorylation of poly r(C) binding protein (PCBP1), has been previously elucidated. The aims of the current study were to determine if the same mechanism is operative in the non-small cell lung cancer (NSCLC) cell line, A549, and to delineate the underlying mechanism. Steady-state transcript and protein expression levels of Dab2 and ILEI were examined in A549 cells treated with TGF-beta for up to 48 h. Induction of translational de-repression in this model was quantified by polysomal fractionation followed by qRT-PCR. The underlying mechanism of isoform-specific activation of Akt2 was elucidated through a combination of co-immunoprecipitation studies. TGF-beta induced EMT in A549 cells concomitant with translational upregulation of Dab2 and ILEI proteins through isoform-specific activation of Akt2 followed by phosphorylation of PCBP1 at serine-43. Our experiments further elucidated that the adaptor protein SchA is phosphorylated at tyrosine residues following TGF-beta treatment, which initiated a signaling cascade resulting in the sequential recruitment of p85 subunit of PI3K and focal adhesion kinase (FAK). The SchA-FAK-p85 complex subsequently selectively recruited and activated Akt2, not Akt1. Inhibition of the p85 subunit through phosphorylated 1257 peptide completely attenuated EMT in these cells. We have defined the underlying mechanism responsible for isoform-specific recruitment and activation of Akt2, not Akt1, during TGF-beta-mediated EMT in A549 cells. Inhibition of the formation of this complex thus represents an important and novel therapeutic target in metastatic lung carcinoma.

语种: 英语
所属项目编号: 2013Z003-C
项目资助者: Study on Railway Workers Chronic Disease Management Network Information Platform
WOS记录号: WOS:000341883500074
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/55198
Appears in Collections:北京大学第一临床医学院_消化内科_期刊论文

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作者单位: 1.Capital Med Univ, Dept Special Med Treatment Resp Dis, Beijing Shijitan Hosp, Beijing, Peoples R China
2.Peking Union Med Coll, Res Dept, Peking Union Med Collage Hosp, Beijing 100021, Peoples R China
3.Chinese Acad Med Sci, Beijing 100730, Peoples R China
4.Peking Univ, Dept Gastroenterol, Hosp 1, Beijing 100871, Peoples R China
5.Capital Med Univ, Dept Crit Care Med, Beijing Shijitan Hosp, Beijing, Peoples R China
6.Chinese Peoples Liberat Army Gen Hosp, Dept Resp Dis, Beijing, Peoples R China
7.Tianjin Fifth Cent Hosp, Dept Endocrinol Dis, Tianjin, Peoples R China

Recommended Citation:
Xue, Xinying,Wang, Xin,Liu, Yuxia,et al. SchA-p85-FAK complex dictates isoform-specific activation of Akt2 and subsequent PCBP1-mediated post-transcriptional regulation of TGF beta-mediated epithelial to mesenchymal transition in human lung cancer cell line A549[J]. TUMOR BIOLOGY,2014,35(8):7853-7859.
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