Volume 25 Issue 5, May 2015: 561-573 | Open Access
ORIGINAL ARTICLES
ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer
Shunrong Ji1,2,3,*, Yi Qin1,2,3,*, Si Shi1,2,3, Xiangyuan Liu4, Hongli Hu4, Hu Zhou5, Jing Gao5, Bo Zhang1,2,3, Wenyan Xu1,2,3, Jiang Liu1,2,3, Dingkong Liang1,2,3, Liang Liu1,2,3, Chen Liu1,2,3, Jiang Long1,2,3, Haijun Zhou6, Paul J Chiao6, Jin Xu1,2,3, Quanxing Ni1,2,3, Daming Gao4 and Xianjun Yu1,2,3
1Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
4Key Laboratory of System Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
5Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
6Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Correspondence: Xianjun Yu( yuxianjun@fudan.edu.cn, yuxianjun@fudanpci.org)
F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-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 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.
10.1038/cr.2015.30
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