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

作　　者：Shunrong Ji Yi Qin Si Shi Xiangyuan Liu Hongli HU Hu Zhou Jing Gao Bo Zhang Wenyan Xu Jiang Liu Dingkong Liang Liang Liu Chen Liu Jiang Long Haijun Zhou Paul J Chiao Jin Xu Quanxing Ni Daming Gao Xianjun Yu 

机构地区：[1]Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China [3]Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China [4]Key Laboratory of System Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [5]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [6]Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

出　　处：《Cell Research》2015年第5期561-573,共13页细胞研究（英文版）

基　　金：We thank HuanYu Xia for assistance in collecting the patient data. We thank Fengqun Zhang, Min Chen, Xiangling Chen, Liyan Gong, Binghai Cui, Huafang Ouyang and Xiaoduo Xie for technical support. This work was supported by the National Natural Science Foundation of China （81372651, 81201900, 81172276 and 81101565）, the Sino-German Center （GZ857）, and the PhD Programs Foundation of the Ministry of Education of China （20120071120104）.

摘　　要：F-box and WD repeat domain-containing 7 （FBW7） is the substrate recognition component of the Skpl-Cull-F- box （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 tum- origenesis. 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.

关 键 词：KRAS pancreatic cancer ERK FBW7 

分 类 号：Q51[生物学—生物化学] Q813