title: ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shunrong
authors.initials: S
authors.lastname: Ji
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Si
authors.initials: S
authors.lastname: Shi
authors.affiliation: Key Laboratory of System Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of System Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Dingkong
authors.initials: D
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Jiang
authors.initials: J
authors.lastname: Long
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Ni
authors.affiliation: Key Laboratory of System Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D044767:Ubiquitin-Protein Ligases; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins