Scientists from Fudan University Medical School have discovered that phosphokinase ERK could accelerate the degradation of FBW7 by phosphorylation. This process influences the function of FBW7 as tumor-inhibiting factor, then accelerate pancreatic cancer development. This study was published in Cell Research.

Pancreatic ductal adenocarcinoma(PDAC), the most common form of pancreatic cancer, is a devastating disease with a 5-year overall survival rate of < 5%, the highest fatality rate among all cancers. The incidence of pancreatic cancer remains equal to its mortality rate.

F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-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 PDAC. Thus, it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer.

In this study, researchers report that FBW7 is rarely mutated and the protein level is significantly downregulated in PDAC, through a mechanism involving an activated Ras-Raf-MEK-ERK signaling pathway. They demonstrate that ERK kinase directly interacts with and phosphorylates FBW7 at Thr205, which leads

Through the study, scientists established a novel link between the oncogenic KRAS-mutant/MAPK/ERK signaling axis and the tumor suppressor FBW7 and revealed the mechanism underlying the impairment of FBW7 function in PDAC. These findings may help develop new therapeutic strategies to treat pancreatic cancer.

Reference:

Ji S, Qin Y, Shi S, et al. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer[J]. Cell research, 2015.