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ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer

文献类型：期刊论文

作者Ji, Shunrong1,4,5; Qin, Yi1,4,5; Shi, Si1,4,5; Liu, Xiangyuan6; Hu, Hongli6; Zhou, Hu3; Gao, Jing3; Zhang, Bo1,4,5; Xu, Wenyan1,4,5; Liu, Jiang1,4,5
刊名CELL RESEARCH
出版日期2015-05
卷号25期号:5页码:561-573
ISSN号1001-0602
关键词KRAS pancreatic cancer ERK FBW7
DOI10.1038/cr.2015.30
文献子类Article
英文摘要F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-Fbox (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.
WOS关键词F-BOX PROTEIN ; UBIQUITIN LIGASE ; C-MYC ; FBXW7 EXPRESSION ; POOR-PROGNOSIS ; MOUSE MODELS ; CYCLIN-E ; DEGRADATION ; DESTRUCTION ; PATHWAY
资助项目National Natural Science Foundation of China[81372651] ; National Natural Science Foundation of China[81201900] ; National Natural Science Foundation of China[81172276] ; National Natural Science Foundation of China[81101565] ; Sino-German Center[GZ857] ; PhD Programs Foundation of the Ministry of Education of China[20120071120104]
WOS研究方向Cell Biology
语种英语
CSCD记录号CSCD:5429293
出版者INST BIOCHEMISTRY & CELL BIOLOGY
WOS记录号WOS:000353917500008
源URL[http://119.78.100.183/handle/2S10ELR8/276555]  
专题分析化学研究室
通讯作者Yu, Xianjun
作者单位1.Fudan Univ, Shanghai Canc Ctr, Dept Pancreat & Hepatobiliary Surg, Shanghai 200032, Peoples R China;
2.Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
4.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China;
5.Fudan Univ, Pancreat Canc Inst, Shanghai 200032, Peoples R China;
6.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Key Lab Syst Biol, Shanghai 200031, Peoples R China;
推荐引用方式
GB/T 7714		 Ji, Shunrong,Qin, Yi,Shi, Si,et al. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer[J]. CELL RESEARCH,2015,25(5):561-573.
APA Ji, Shunrong.,Qin, Yi.,Shi, Si.,Liu, Xiangyuan.,Hu, Hongli.,...&Yu, Xianjun.(2015).ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.CELL RESEARCH,25(5),561-573.
MLA Ji, Shunrong,et al."ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer".CELL RESEARCH 25.5(2015):561-573.

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来源：上海药物研究所

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