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ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.
- Source :
-
Cell research [Cell Res] 2015 May; Vol. 25 (5), pp. 561-73. Date of Electronic Publication: 2015 Mar 10. - Publication Year :
- 2015
-
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.
- Subjects :
- Animals
Cell Cycle Proteins genetics
Cell Line, Tumor
Cell Proliferation genetics
Cell Proliferation physiology
Extracellular Signal-Regulated MAP Kinases genetics
F-Box Proteins genetics
F-Box-WD Repeat-Containing Protein 7
Humans
Mice
Mutation
Pancreatic Neoplasms genetics
Phosphorylation
Proteasome Endopeptidase Complex metabolism
Protein Binding
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins p21(ras)
Real-Time Polymerase Chain Reaction
Ubiquitin-Protein Ligases genetics
Ubiquitination
ras Proteins genetics
Cell Cycle Proteins metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
F-Box Proteins metabolism
Pancreatic Neoplasms metabolism
Proto-Oncogene Proteins metabolism
Ubiquitin-Protein Ligases metabolism
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1748-7838
- Volume :
- 25
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell research
- Publication Type :
- Academic Journal
- Accession number :
- 25753158
- Full Text :
- https://doi.org/10.1038/cr.2015.30