title: Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer.
abstract: 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 FBXW7α 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 tumor-suppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer.Cancer Res; 77(8); 1983-96. ©2017 AACR.
authors.affiliation: Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, PR China.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, PR China.
authors.forename: Pengju
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, PR China.|Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, PR China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Shandong, PR China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California. gwwei@yahoo.com JHMao@lbl.gov.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Department of Human Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Shandong, PR China. gwwei@yahoo.com JHMao@lbl.gov.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D060066:Protein Interaction Maps; D020033:Protein Isoforms; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C101633:PA2G4 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; D046988:Proteasome Endopeptidase Complex