Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer

作者：Wang, Yuli; Zhang, Pengju; Wang, Yunshan; Zhan, Panpan; Liu, Chunyan; Mao, Jian-Hua^*; Wei, Guangwei^*

来源：Cancer Research, 2017, 77(8): 1983-1996.

DOI：10.1158/0008-5472.CAN-16-2246

• F-BOX PROTEIN
• EPITHELIAL-MESENCHYMAL TRANSITION
• TUMOR-SUPPRESSOR GENE
• FBW7 UBIQUITIN LIGASE
• CELL-PROLIFERATION
• POOR-PROGNOSIS
• CYCLIN-E
• EXPRESSION
• DEGRADATION
• PHOSPHORYLATION

The ErbB3 receptor-binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7a to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumorsuppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoformspecific functions of EBP1 in cancer.

• 出版日期2017-4-15
• 单位山东大学