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ERK induces degradation of tumor suppressor FBW7 in pancreatic cancer

 

F-box and WD repeat domain-containing 7  (FBW7) is a main tumor suppressor that promotes degradation of multiple oncoproteins. Gene encoding FBW7 is frequently absent or mutant in many human cancers, such as gastric cancer, colon cancer, breast carcinoma, esopageal cell carcinoma as well as intrahepatic cholangiocarcinoma, except in pancreatic ductal adenocarcinoma (PDAC). Ji et al. demonstrated a correlation between low expression of FBW7 and ERK activation in pancreatic cancer. The article was published in Cell Research.

 

The activation of ERK is mainly due to KRAS mutations in pancreatic cancer. Mechanically, ERK phosphorylated FBW7 at Thr205 by directly binding to FBW7. The phosphorylation leads to FBW7 ubiquitination and proteasomal degradation. On the other hand, mutant FBW7 with phospho-deficient T205A is resistant to ERK activation and significantly inhibit cell proliferation and tumor development in pancreatic cancer. The findings indicate the low level of FBW7 is not due to mutation of FBW7 gene, but the significant downregulation of its protein level in PDAC, via activation of Ras-Raf-MEK-ERK signaling pathway, facilitating the development of new therapeutic strategies for PDAC.

 

Reference:
Cell Res. 2015 Mar 10. doi: 10.1038/cr.2015.30.

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ERK MEK Proteasome