FBW7 mediates the ubiquitination of many important proteins, including proto-oncoproteins, such as cyclin E, Notch, mTOR, c-Jun and c-Myc, which play important roles in the cell cycle, cell proliferation and differentiation. proteins that play important roles in cell cycle, cell proliferation and differentiation. Therefore, inactivation of FBW7 can cause the development of many kinds of malignant tumors, such as gastric cancer, colon cancer, breast cancer and liver cancer. Professor Yu Xianjuan from Shanghai Cancer Hospital published a research paper on FBW7 and pancreatic ductal adenocarcinoma (PDAC) in Cell Research. His research team found that the phosphokinase ERK can phosphorylate FBW7 to promote its degradation, a process that affects the function of FBW7 as a tumor suppressor and induces pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is a common and dreaded form of pancreatic cancer, with a 5-year survival rate of less than 5% and one of the highest mortality rates of all cancers. Due to the lack of effective early detection methods and the high rate of metastasis after the initial diagnosis of this cancer, only 15-20% of patients are able to undergo resection. Therefore, there is an urgent need to improve the practicability of clinical treatment, as well as a deeper understanding of the molecular mechanisms underlying the development of PDAC. Based on earlier studies, we know that FBW7 is closely related to the Ras/Raf/MEK/ERK signaling pathway, but it is not clear how the expression level of FBW7 is regulated. In the present study, scientists first found that low FBW7 expression in pancreatic cancer clinical samples was significantly associated with ERK activation, which is mainly due to KRAS mutations in pancreatic cancer. Further studies revealed that ERK was able to directly phosphorylate threonine at position 205 of FBW7, promoting its auto-ubiquitination degradation. The researchers then demonstrated that the T205A mutant of FBW7 resisted phosphorylation by ERK and led to a decrease in the expression level of one of the important proto-oncogenes, c-Myc, resulting in a significant inhibition of pancreatic cancer cell proliferation and tumorigenesis. Overall these results reveal how oncogene KRAS mutations promote pancreatic cancer progression by suppressing the tumor suppressor FBW7, providing a good molecular basis for clinical practice treatment of pancreatic cancer. How did the article identify the phosphorylation site of FBW7 and the phosphorylation of FBW7 by ERK? Based on recent studies, the authors identified Thr205-Pro206 as the only potential phosphorylation site on FBW7, and then determined whether Thr205 was the exact activation site by two aspects: 1) Thr205 on FBW7 protein significantly reduced the phosphorylation level of FBW7 after binding to specific antibodies; 2) constructing a T205A mutant of FBW7 and found that it was difficult to be phosphorylated. In a follow-up experiment, the authors overexpressed the continuously phosphorylated ERK protein and detected increased phosphorylation levels of FBW7 and decreased phosphorylation levels of FBW7-T205A.